The growth and migration of neurons require continuous remodelling of the neuronal cytoskeleton, providing a versatile cellular framework for force generation and guided movement, in addition to ...structural support. Actin filaments and microtubules are central to the dynamic action of the cytoskeleton and rapid advances in imaging technologies are enabling ever more detailed visualisation of the dynamic intracellular networks that they form. However, these filaments do not act individually and an expanding body of evidence emphasises the importance of actin–microtubule crosstalk in orchestrating cytoskeletal dynamics. Here, we summarise our current understanding of the structure and dynamics of actin and microtubules in isolation, before reviewing both the mechanisms and the molecular players involved in mediating actin–microtubule crosstalk in neurons.
We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international ...standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.
FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio HR of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.
Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.
26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.
National Institute for Health Research Health Technology Assessment Programme.
In The Lancet Oncology, Vratislav Strnad and colleagues,1 report the long-term results of their multicentre, phase 3 trial investigating accelerated partial breast irradiation (APBI) using ...multicatheter brachytherapy for patients aged 40 years or older with early breast cancer, with a median follow-up of 10·36 years. 1328 women were randomly assigned to receive 50 Gy whole-breast irradiation delivered in 25 daily fractions over 5 weeks plus a 10 Gy tumour bed boost (n=673) or APBI (n=655) delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Burger/Phanie/Science Photo Library This high-quality study adds to other longer-term ipsilateral breast tumour recurrence results from mainly external-beam APBI versus whole-breast irradiation trials, namely the Florence trial (n=520, median follow-up 10·7 years),2 NSABP B-39/RTOG 0413 (n=4216, median follow-up 10·2 years),3 and the RAPID trial (n=2135, median follow-up 8·6 years).4 These trials show similar, low local recurrence rates with no difference in overall survival using APBI or whole-breast irradiation, for patients at low-risk of breast cancer recurrence, and we await the 10-year results of IMPORT Low (ISRCTN12852634) and the ongoing Early Breast Cancer Triallist Group individual patient data meta-analysis of APBI in due course. Additionally, research has focused on de-escalation, but some patients report substantial toxicity with endocrine therapy. ...we should also investigate de-escalation of systemic therapy using health-related quality of life endpoints where survival outcomes are equivalent.10 In conclusion, both brachytherapy and external-beam APBI radiotherapy are important and relevant treatments today for patients with low-risk breast cancer.
The specification of an axon and its subsequent outgrowth are key steps during neuronal polarization, a prerequisite to wire the brain. The Rho-guanosine triphosphatase (GTPase) RhoA is believed to ...be a central player in these processes. However, its physiological role has remained undefined. Here, genetic loss- and gain-of-function experiments combined with time-lapse microscopy, cell culture, and in vivo analysis show that RhoA is not involved in axon specification but confines the initiation of neuronal polarization and axon outgrowth during development. Biochemical analysis and super-resolution microscopy together with molecular and pharmacological manipulations reveal that RhoA restrains axon growth by activating myosin-II-mediated actin arc formation in the growth cone to prevent microtubules from protruding toward the leading edge. Through this mechanism, RhoA regulates the duration of axon growth and pause phases, thus controlling the tightly timed extension of developing axons. Thereby, this work unravels physiologically relevant players coordinating actin-microtubule interactions during axon growth.
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•RhoA restrains axon initiation and growth independent of specification•Myosin II is the physiological target of RhoA during axon growth•RhoA/myosin-II-dependent actin arcs restrict microtubule advance in the growth cone•RhoA instructs the duration of growth and pause phases in developing axons
Combining genetic, molecular, pharmacological, and biochemical approaches together with super-resolution and live-cell microscopy, Dupraz et al. show that RhoA physiologically limits axon outgrowth by activating myosin-II-dependent actin arc formation to restrict microtubule protrusion toward the growth cone leading edge.
Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic ...organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1–9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular “head-to-stalk” (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.
•Structural studies reveal a major ring-like conformation for PlxnA ectodomains•PlxnA ectodomains make head-to-stalk cis-interactions in vitro and on cell surface•Disruption of PlxnA cis-interactions induces cell and growth cone collapse•PlxnA ectodomain structure and interaction enable autoinhibition and activation
PlxnA signaling, important in nervous system development and plasticity, requires multi-leveled regulation. Kong et al. reveal a novel mechanism for PlxnAs, in which autoinhibition pre- and activation post-ligand binding are achieved through distinct conformations and cis-interactions of the receptor ectodomains.
High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions ...with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy.
The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related ...complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
...boost volumes should be small and targeted. ...it is necessary that patients are empowered to exercise choices that reflect their individual preferences. RJ is funded by the Susan G Komen ...Foundation and has received grants paid to her institution for unrelated work from the National Institutes of Health, the Doris Duke Foundation, the Greenwall Foundation, the American Cancer Society, and Blue Cross Blue Shield of Michigan for the Michigan Radiation Oncology Quality Consortium; was principal investigator on a contract to conduct an investigator-initiated study with Genentech on the financial toxicity experienced by patients with breast cancer, paid to her institution; received personal fees for an advisory or grant review service from the National Institutes of Health, the Doris Duke Foundation, and the Greenwall Foundation; served as an expert witness for Sherinian and Hasso, Dressman Benzinger LaVelle, and Kleinbard, unrelated to the topic of this Comment; and has stock options as compensation for her advisory board role in Equity Quotient, a company that evaluates culture in health-care companies unrelated to the topic of this Comment.
As we mark 150 years since the birth of Marie Curie, we reflect on the global advances made in radiation oncology and the current status of radiation therapy (RT) research. Large-scale international ...RT clinical trials have been fundamental in driving evidence-based change and have served to improve cancer management and to reduce side effects. Radiation therapy trials have also improved practice by increasing quality assurance and consistency in treatment protocols across multiple centres. This review summarises some of the key RT practice-changing clinical trials over the last two decades, in four common cancer sites for which RT is a crucial component of curative treatment: breast, lung, urological and lower gastro-intestinal cancer. We highlight the global inequality in access to RT, and the work of international organisations, such as the International Atomic Energy Agency (IAEA), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the United Kingdom National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad), that aim to improve access to RT and facilitate radiation research. We discuss some emerging RT technologies including proton beam therapy and magnetic resonance linear accelerators and predict likely future directions in clinical RT research.
A major driver for the recent investment surge in bispecific antibody (bsAb) platforms and products is the multitude of distinct mechanisms of action that bsAbs offer compared to a combination of two ...monoclonal antibodies. Four bsAb products were granted first regulatory approvals in the US or EU during 2023 and the biopharmaceutical industry pipeline is brimming with bsAb candidates across a broad range of therapeutic applications. In previously reported bsAb discovery campaigns, following a hypothesis-based choice of two specific target proteins, selections and screening activities have often been performed in mono-specific formats. The conversion to bispecific modalities has usually been positioned toward the end of the discovery process and has involved small numbers of lead molecules, largely due to challenges in expressing, purifying, and analyzing large numbers of bsAbs. In this review, we discuss emerging strategies to facilitate the production of expanded bsAb panels, focusing particularly upon combinatorial methods to generate bsAb matrices. Such technologies will enable screening in. bispecific formats at earlier stages of discovery campaigns, not only widening the accessible protein space to maximize chances of success, but also advancing empirical bi-target validation activities to assess initial target selection hypotheses.
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