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A B S T R A C T PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P Ͻ .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinibassociated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Covalent modification of cellular proteins by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport, signal transduction, stress response and cell-cycle progression. But, in contrast to ubiquitylation, sumoylation does not tag proteins for degradation, but seems to enhance their stability or modulate their subcellular compartmentalization.

The PML protein, identified first as part of the oncogenic PML-RARα chimera in acute promyelocytic leukemia (APL), concentrates within discrete subnuclear structures, corresponding to some types of nuclear bodies. These structures are disrupted in APL cells, and retinoic acid (RA) can trigger their reorganization, correlating with its therapeutic effect in this type of leukemia. Recently, arsenic trioxide (As 2 O 3 ) was identified as a potent antileukemic agent which, similarly to RA, induces complete remissions in APL patients. Here we show that, in APL cells, As 2 O 3 triggers rapid degradation of PML-RARα and provokes the restoration of intact nuclear bodies. In non-APL cells, the ubiquitin-like protein SUMO-1 is covalently attached to a subset of wild-type PML in a reversible and phosphorylation-dependent manner. The unmodified form of PML is found in the soluble nucleoplasmic fraction, whereas the SUMO-1-polymodified forms of PML are compartmentalized exclusively in the PML nuclear bodies. As 2 O 3 administration strikingly increases the pool of SUMO-1-PML conjugates that, subsequently, accumulate in enlarged nuclear bodies. In contrast to PML-RARα, the overall amount of PML seems to remain unaltered up to 36 h following As 2 O 3 treatment. These findings indicate that the conjugation of PML with SUMO-1 modulates its intracellular localization and suggest that post-translational modification by SUMO-1 may be more generally involved than previously suspected in the targeting of proteins to distinct subcellular structures. They provide additional evidence that the role of 'ubiquitin-like' post-translational modification is not limited to a degradation signal.

In 1970 V. Efimov predicted a puzzling quantummechanical effect that is still of great interest today. He found that three particles subjected to a resonant pairwise interaction can join into an infinite number of loosely bound states even though each particle pair cannot bind. Interestingly, the properties of these aggregates, such as the peculiar geometric scaling of their energy spectrum, are universal, i.e. independent of the microscopic details of their components. Despite an extensive search in many different physical systems, including atoms, molecules and nuclei, the characteristic spectrum of Efimov trimer states still eludes observation. Here we report on the discovery of two bound trimer states of potassium atoms very close to the Efimov scenario, which we reveal by studying three-particle collisions in an ultracold gas. Our observation provides the first evidence of an Efimov spectrum and allows a direct test of its scaling behaviour, shedding new light onto the physics of few-body systems.From nuclei, atoms and molecules up to galaxies, our complex world is made up of many kinds of aggregates whose properties depend on the details of the interactions between their components. This scenario is expected to drastically change as one moves to the world of few neutral quantum particles. The physics of these systems is typically dominated by two-body interactions, which in the limit of vanishing collision energies can be described by a single parameter, namely the s-wave scattering length, independently from the nature of the particles and of the microscopic shape of their interaction 1,2 . If the two-body scattering length becomes resonantly large, the binding of few such particles into larger aggregates is predicted to become universal, in the sense that its properties depend only on the scattering length and few other global parameters 3 .These expectations have been so far verified only for twobody bound states 2 , and even the seemingly simple case of three particles is still under investigation. In this frame, a landmark theoretical result was obtained in 1970 by Efimov 4,5 . He extended previous studies 6 to show that three identical bosons with large two-body scattering length a, even without two-body bound states, can form weakly bound trimer states with size greatly exceeding the characteristic range r 0 of the two-body potential. The binding properties of such states follow a universal behaviour, regardless of the microscopic peculiarities of their components and of their interaction. Efimov indeed identified an effective three-particle interaction potential of the form -(s 0 2 +1/4)/R 2 , where R is the overall size of the three-body system and s 0 1.00624 is a universal parameter 4 . This simple potential is known to support an infinite number of bound states whose energy spectrum exhibits a peculiar geometric scaling where two consecutive states are linked by the relation E n =E n-1 exp(-2/s 0 ). This perfect scaling is predicted to apply only for the special case of a system with infinite...

The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.DOI: http://dx.doi.org/10.7554/eLife.25555.001

The activity of the p53 tumor suppressor protein and the c-Jun protooncogene is regulated by posttranslational modifications, such as phosphorylation or ubiquitination. In addition, covalent attachment of the ubiquitin-like modifier SUMO appears to modulate their transcriptional activity. Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme. Here, we show that two members of the PIAS family, PIAS1 and PIASx␤, act as specific E3-like ligases that promote sumoylation of p53 and c-Jun in vitro and in vivo. The PIAS proteins physically interact with both p53 and c-Jun. In addition, they bind to Ubc9, suggesting that they recruit the E2 enzyme to their respective substrate. The SUMO ligase activity requires the conserved zinc-finger domain, which is distantly related to the essential RING-finger motif, found in a subset of ubiquitin ligases. Furthermore, similar to RING-type ubiquitin ligases, PIASx␤ can catalyze its own modification. Hence, these data further extend the analogy between the ubiquitin and SUMO pathway. Strikingly, PIAS proteins strongly repress the transcriptional activity of p53, suggesting that the PIAS-SUMO pathway plays a crucial role in the regulation of p53 and presumably other transcription factors. Many cellular key functions are regulated by the covalent modification of proteins with the ubiquitin-like SUMO-1 modifier (1-3). Two important examples are the transcriptional activity of the c-Jun protooncogene and the p53 tumor suppressor, which seem to be regulated by sumoylation (4-6). Mammalian SUMO-1 and its close relatives, SUMO-2 and SUMO-3, are about 18% identical to ubiquitin and are conjugated via an enzymatic cascade that requires a SUMO-specific, heterodimeric E1-activating enzyme (Aos1͞Uba2) and a single E2-type conjugating enzyme, Ubc9. In the ubiquitin pathway, at least one additional factor, called E3 or ubiquitin ligase, is required for substrate recognition and formation of an isopeptide bond between ubiquitin and the target protein. Because the SUMO-specific E2 enzyme Ubc9 has been shown to physically interact with almost all known SUMO substrates in yeast twohybrid assays, Ubc9 was considered to be sufficient for substrate recognition.Very recently, however, in the yeast Saccharomyces cerevisiae, the Siz1 and Siz2 proteins were identified as E3-like factors that promote SUMO conjugation to yeast proteins, in particular to proteins of the septin family (7-9). Siz proteins are homologous to members of the mammalian PIAS (protein inhibitor of activated Stat) family of proteins. In humans, this family consists of at least five members: PIAS1, PIAS3, the ␣ and ␤ splice variants of PIASx, and PIASy (10). PIAS proteins were initially identified as specific inhibitors of Stat transcription factors. PIAS1 and PIAS3 block the DNA binding activity of activated Stat1 and Stat3, respectively, and inhibit Stat-mediated transcription (11, 12). Subsequentl...

Radioembolization has been demonstrated to allow locoregional therapy of patients with hepatocellular carcinoma not eligible for transarterial chemoembolization or other local therapies. The aim of this study was to validate evidence of the safety and efficacy of this treatment in a European sample of patients with advanced hepatocellular carcinoma (HCC). Therefore, 108 consecutive patients with advanced HCC and liver cirrhosis were included. Yttrium-90 (Y-90) microspheres were administered in a lobar fashion over the right or left branch of the hepatic artery. The response to treatment was evaluated by computed tomography (CT) imaging applying Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria with recent European Association for the Study of the Liver / National Cancer Institute (EASL/NCI) amendments. Time to progression (TTP) and overall survival were estimated by the Kaplan-Meier method. In all, 159 treatment sessions were performed ranging between one to three treatments per patient. The mean radiation dose per treatment was 120 (618) Gy. According to EASL criteria, complete responses were determined in 3% of patients, partial responses in 37%, stable disease 53%, and primary progression in 6% of patients. TTP was 10.0 months, whereas the median overall survival was 16.4 months. No lung or visceral toxicity was observed. The most frequently observed adverse events was a transient fatigue-syndrome. Conclusion: Radioembolization with Y-90 glass microspheres for patients with advanced HCC is a safe and effective treatment which can be utilized even in patients with compromised liver function. Because TTP and survival appear to be comparable to systemic therapy in selected patients with advanced HCC, randomized controlled trials in combination with systemic therapy are warranted.