The regulation of mRNA deadenylation constitutes a pivotal mechanism of the post-transcriptional control of gene expression. Here we show that the antiproliferative protein Tob, a component of the ...Caf1-Ccr4 deadenylase complex, is involved in regulating the expression of the proto-oncogene c-myc. The c-myc mRNA contains cis elements (CPEs) in its 3'-untranslated region (3'-UTR), which are recognized by the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB recruits Caf1 deadenylase through interaction with Tob to form a ternary complex, CPEB-Tob-Caf1, and negatively regulates the expression of c-myc by accelerating the deadenylation and decay of its mRNA. In quiescent cells, c-myc mRNA is destabilized by the trans-acting complex (CPEB-Tob-Caf1), while in cells stimulated by the serum, both Tob and Caf1 are released from CPEB, and c-Myc expression is induced early after stimulation by the stabilization of its mRNA as an 'immediate-early gene'. Collectively, these results indicate that Tob is a key factor in the regulation of c-myc gene expression, which is essential for cell growth. Thus, Tob appears to function in the control of cell growth at least, in part, by regulating the expression of c-myc.
Background
Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, ...Kaplan–Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3–6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC.
Methods
We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3
log(D
0
/D
pre
)/t
, where
D
0
and
D
pre
are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and
t
is time, with 1
t
defined as 4 weeks.
Results
Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (
p
= 0.01) and OS (
p
< 0.01).
Conclusions
These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.
Abstract
In the low energy ring (LER) for positrons in the SuperKEKB, a vertical beam size blow-up was observed when the bunch current was approximately 1 mA. If a beam size blow-up occurs, the ...design luminosity cannot be achieved. Therefore, beam size blow-ups must be pre-vented. According to calculations, the bunch current threshold of the transverse mode coupling instability (TMCI) is 2 mA or more, and the observed value is 50% or smaller. Ordinary TMCI cannot explain this vertical beam size blow-up. This paper shows that the cause of the vertical beam size blow-up can be determined by analyzing factors such as beam oscillation. The study results showed that the vertical beam size blow-up in the LER was caused by a -1 mode instability.
Recanalization after coil embolization is widely studied. However, there are limited data on how recanalized aneurysms rupture. Herein, we describe our experience with the rupture of recanalized ...aneurysms and discuss the type of recanalized aneurysms at greatest rupture risk.
A total of 426 unruptured aneurysms and 169 ruptured aneurysms underwent coil embolization in our institution between January 2009 and December 2017. Recanalization occurred in 38 (8.9%) of 426 unruptured aneurysms (unruptured group) and 37 (21.9%) of 169 ruptured aneurysms (ruptured group). The Modified Raymond-Roy classification on DSA was used to categorize the recanalization type. Follow-up DSA was scheduled until 6 months after treatment, and follow-up MRA was scheduled yearly. If recanalization was suspected on MRA, DSA was performed.
In the unruptured group, the median follow-up term was 74.0 months. Retreatment for recanalization was performed in 18 aneurysms. Four of 20 untreated recanalized aneurysms (0.94% of total coiled aneurysms) ruptured. In untreated recanalized aneurysms, class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (
= .025). In the ruptured group, the median follow-up term was 28.0 months. Retreatment for recanalization was performed in 16 aneurysms. Four of 21 untreated recanalized aneurysms (2.37% of total coiled aneurysms) ruptured. Class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (
= .02).
The types of recanalization after coil embolization may be predictors of rupture. Coiled aneurysms with class IIIb recanalization should undergo early retreatment because of an increased rupture risk.
The SuperKEKB e+ e− collider uses highly focused ultra-low emittance bunches colliding every 4 ns to reach a very high luminosity of 8 × 1035cm−2s−1. It is essential to have an orbit feedback system ...at the Interaction Point (IP) to maintain the optimum overlap between the colliding beams in the presence of ground motion disturbances. For the horizontal motion, a luminosity monitoring system, based on measuring the rate of the Bhabha process at vanishing scattering angle, is developed as input signal to the feedback system. The relative precision needed for this monitor is studied in detail, for the different successive stages of luminosity operation, based on a full simulation of this system, including the detector, DAQ, lock-in amplifier, and feedback control.
An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based ...chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting.
This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0).
Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed.
Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.
•Paclitaxel plus biweekly cetuximab demonstrated promising efficacy for patients with R/M-HNSCC.•ORR was 69.6%, which met the primary endpoint.•PFS and OS were 5.5 and 13.3 months, respectively.•This combination is a potential treatment option after progression on platinum and PD-1 antibody.
SuperKEKB is an electron–positron asymmetric-energy double-ring collider, which was built in Japan. It has been operated to explore new phenomena in B-meson decays. Hence, extremely higher luminosity ...is required. A collision scheme of low emittance with a large Piwinski angle called a “nano-beam scheme” has been adopted to achieve higher luminosity by squeezing the vertical beta function at the interaction point to be smaller than the bunch length. A “crab waist collision scheme” proposed by P. Raimondi et al. has also been adopted to improve the luminosity performance. The article presents an overview of the operation of the nano-beam and crab waist collision schemes at SuperKEKB.
SuperKEKB is a very high luminositye+e−collider consisting of a low energy ring (LER) of positrons of 4 GeV and a high energy ring (HER) of electrons of 7 GeV. The high luminosity will be achieved ...thanks to the nanobeam scheme, where very strongly focused beams (σy=60nm) will collide at a large crossing angle of 83 mrad. To maintain high luminosity operation, fast luminosity monitoring is essential in the presence of dynamic instabilities, for feedback and optimization. Fast luminosity monitors consisting of a single crystalline diamond sensor (LAL), a Cherenkov and scintillator detector (KEK) were placed in both rings downstream of the IP (interaction point) to measure the signal from the radiative Bhabha process at zero photon scattering angle (σ≈200mbarn). During single beam commissioning of SuperKEKB, the fast luminosity monitors were used as beam loss monitors to measure the single beam losses (beam-gas bremsstrahlung, Touschek scattering, Coulomb scattering). In this paper, a detailed description of the experimental setup, the data acquisition scheme, the data analysis and the comparison with the simulation for the diamond sensors, will be reported.
Assessment of renal function is important for safe cancer chemotherapy, and eligibility criteria for clinical trials often include creatinine clearance. However, creatinine clearance overestimates ...glomerular filtration rate, and various new formulae have been proposed to estimate glomerular filtration rate. Because these were developed mostly in patients with chronic kidney disease, we evaluated their validity in cancer patients without kidney disease.
Glomerular filtration rate was measured by inulin clearance in 45 Japanese cancer patients, and compared with creatinine clearance measured by 24-h urine collection as well as that estimated by the Cockcroft-Gault formula, Japanese estimated glomerular filtration rate developed in chronic kidney disease patients, the Modification of Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration equation. The Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration equations were adjusted for the Japanese population by multiplying by 0.808 and 0.813, respectively.
The mean inulin clearance was 79.2 ± 18.7 ml/min/1.73 m(2). Bias values to estimate glomerular filtration rate for Japanese estimated glomerular filtration rate, the Cockcroft-Gault formula, creatinine clearance measured by 24-h urine collection, the 0.808 × Modification of Diet in Renal Disease study equation and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation were 0.94, 9.75, 29.67, 5.26 and -0.92 ml/min/1.73 m(2), respectively. Precision (root-mean square error) was 14.7, 22.4, 39.8, 16.0 and 14.1 ml/min, respectively. Of the scatter plots of inulin clearance versus each estimation formula, the Japanese estimated glomerular filtration rate correlated most accurately with actual measured inulin clearance.
The Japanese estimated glomerular filtration rate and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation estimated glomerular filtration rate with lower bias and higher precision than the other formulae. We therefore propose Japanese estimated glomerular filtration rate for the estimation of glomerular filtration rate in Japanese cancer patients.
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