Summary
We evaluate 38 elderly women who had received long-term denosumab treatment after stopping the drug. Taking into account the gain during treatment and the loss after stopping treatment, they ...lost 35.5% of the total gain in the spine, 44.6% of the total gain in the femoral neck, and 103.3% in the total hip.
Introduction
Denosumab (DMAb) is a soluble inhibitor of the receptor activator of nuclear factor-kappaB ligand (RANKL) and, therefore, does not incorporate into the bone matrix. Consistently, DMAb discontinuation is associated with reversal of the effects attained with treatment.
Purpose
The aim of this study is to assess changes in BMD after a year of discontinuation of DMAb in a group of postmenopausal women treated with DMAb for 7 or 10 years. Secondly, is to evaluate the occurrence of fragility fractures.
Methods
Women who had participated in the FREEDOM study and its extension were invited to participate in this follow-up study. BMD at LS and hip and spine X-rays were obtained. Results were compared to the last value obtained while in treatment to assess changes after discontinuation.
Results
Thirty-eight women, mean age: 81 ± 3.4 years completed study procedures; none had received bisphosphonates after stopping DMAb. Mean gap time between DMAb last dose and the follow-up visit was 17 months (range 16–20 months). Bone mineral density (BMD) decreased significantly in all regions: − 8.1% in LS, − 6% in FN, and − 8.4% in TH. Five (5/38, 13.15%) patients had a fragility fracture, one suffered a wrist fracture, and four experienced vertebral fractures. Three patients suffered one vertebral fracture and one of them had two vertebral fractures. Laboratory results showed the following mean values: CTX = 996 ± 307 pg/ml (normal values 550 ± 226 pg/ml); osteocalcin = 55.2 ± 18.6 ng/ml (normal value 42 ng/ml); and 25 OH vitamin
D
= 23.7 ± 6.9 ng/ml.
Conclusion
Our results describe the rapid bone loss occurring after cessation of denosumab treatment. Further studies are needed to assess if patients have a higher risk of fracture after stopping DMAb and if so, which patients have the highest risk, and assess the role of transitioning to bisphosphonates in the long term.
Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or ...metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.
•Patients who receive antiandrogen treatments are more likely to develop CRPC.•A genomic landscape study has identified aberrant epigenetic events in CRPC and NEPC development.•Epigenetic targeting may represent an alternative therapeutic regimen for advanced prostate cancer.•Ongoing preclinical and clinical trials have shed light on the advantage of combination therapies.
Highlights • Evasion of immune surveillance, a process defined immune-editing, leads to RCC malignant progression. • The PD-1/PD-L1 axis inhibition by targeted-antibodies, increases T-cell ...proliferation and anti-tumor activity. • PD-1 and PD-L1 inhibitors have been tested in RCC, alone or combined with anti-VEGF/VEGFR drugs or other immunotherapies. • We discuss the role of PD-1/PD-L1 in RCC, focusing on current clinical studies and future perspectives.
Summary
Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off ...treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options.
Introduction
In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course.
Methods
In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ − 2.0 and ≥ − 3.5) received romosozumab or placebo (month 0–24) followed by placebo or denosumab (month 24–36); participants then received a year of romosozumab (month 36–48).
Results
Of 167 participants who entered the month 36–48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (
n
= 19) increased BMD by amounts similar to their initial treatment (month 0–12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (
n
= 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses.
Conclusions
After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.
At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and ...segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role. In this review, we provide an overview of DNA linkages between sister chromatids, from their origin to their resolution, and we discuss the consequences of a failure in their detection and processing and speculate on their potential role.
The Crotone Basin was generated in the late Cenozoic as a forearc basin of the Ionian arc‐trench system. New data are gained through detailed field mapping, high‐resolution stratigraphic analysis of ...a key area and examination of offshore well data and seismic reflection profiles. Major unconformities divide the basin fill into major sequences, which reveal a three‐stage internal organization thought to reflect geodynamic events of the Calabrian arc and backarc area closely. The first stage is characterized by extensional block faulting and uplift followed by rapid drowning during high subsidence and transtension in the basin along a major NNW‐ to NW‐striking fault system. This stage is interpreted to reflect resumption of rollback after an episode of slab tearing triggered by transitory docking of continental lithosphere in the trench. The initial uplift is inferred to reflect decoupling and rebound after the transitory coupling phase. The second stage is characterized by increased subsidence and continued extension/transtension. This trend presumably reflects a decreasing rate of rollback resulting from a tendency towards viscous coupling after acceleration of slab downwelling. The third stage is characterized by short‐lived transpression along major shear zones and local inversion of former basins. This is inferred to reflect entrance into the trench of buoyant continental lithosphere, resulting in significant deceleration of slab rollback and consequently a break in, or slowing of, backarc extension, and predominance of the effects of compression related to Africa–Europe convergence. Overall, the above evolution resulted in the formation of a progressively narrower and rapidly retreating slab, inducing extreme rates of backarc extension, and may have played a critical role in determining the intermittent nature of the backarc rifting.
Cohesin organizes the genome by forming intra-chromosomal loops and inter-sister chromatid linkages. During gamete formation by meiosis, chromosomes are reshaped to support crossover recombination ...and two consecutive rounds of chromosome segregation. Here we show that meiotic chromosomes are organised into functional domains by Eco1 acetyltransferase-dependent positioning of both chromatin loops and sister chromatid cohesion in budding yeast. Eco1 acetylates the Smc3 cohesin subunit in meiotic S phase to establish chromatin boundaries, independently of DNA replication. Boundary formation by Eco1 is critical for prophase exit and for the maintenance of cohesion until meiosis II, but is independent of the ability of Eco1 to antagonize the cohesin-release factor, Wpl1. Conversely, prevention of cohesin release by Wpl1 is essential for centromeric cohesion, kinetochore monoorientation and co-segregation of sister chromatids in meiosis I. Our findings establish Eco1 as a key determinant of chromatin boundaries and cohesion positioning, revealing how local chromosome structuring directs genome transmission into gametes.
How are teams able to cope with environmental threats? Why are some teams better than others in facing this challenge? This paper addresses these questions by investigating two drivers of team ...resilience: the team size and the density of social interactions among team members. We adopt a complex system approach and employ a model of team decision-making where collective dynamics of team members are governed by a continuous-time Markov process. The model simulates team performance in complex and turbulent environments. It is used to measure the resilient ability of team to quickly adapt to disturbance and secure a new more desirable condition. Scenarios characterized by increasing levels of complexity and turbulence are simulated, and the resilience performance is calculated and compared. Results show that the team size negatively affects the team resilience, whilst the density of social interactions plays a positive influence, especially at a high level of complexity. We also find that both the magnitude and the frequency of disturbance moderate the relationship between team size/density and the team resilience.
Transradial access for neurointerventional procedures has been proved a safer and more comfortable alternative to femoral artery access. We present our experience with transradial (distal ...radial/anatomic snuffbox and radial artery) access for treatment of intracranial aneurysms using all 3 FDA-approved flow diverters.
This was a high-volume, dual-center, retrospective analysis of each institution's data base between June 2018 and June 2020 and a collection of all patients treated with flow diversion via transradial access. Patient demographic information and procedural and radiographic data were obtained.
Seventy-four patients were identified (64 female patients) with a mean age of 57.5 years with a total of 86 aneurysms. Most aneurysms were located in the anterior circulation (93%) and within the intracranial ICA (67.4%). The mean aneurysm size was 5.5 mm. Flow diverters placed included the Pipeline Embolization Device (Flex) (PED,
= 65), the Surpass Streamline Flow Diverter (
= 8), and the Flow-Redirection Endoluminal Device (FRED,
= 1). Transradial access was successful in all cases, but femoral crossover was required in 3 cases (4.1%) due to tortuous anatomy and inadequate support of the catheters in 2 cases and an inability to navigate to the target vessel in a patient with an aberrant right subclavian artery. All 71 other interventions were successfully performed via the transradial approach (95.9%). No access site complications were encountered. Asymptomatic radial artery occlusion was encountered in 1 case (3.7%).
Flow diverters can be successfully placed via the transradial approach with high technical success, low access site complications, and a low femoral crossover rate.
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