The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in ...myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca
2+
-dependent stiffening of titin stretched during eccentric muscle contractions. Findings suggest that titin stiffness is a principal regulator of the contractile behavior of striated muscle. Physiological or pathological changes to titin stiffness therefore affect contractility. Taken together, titin emerges as a linker element between passive and active myocyte properties.
Abstract
US has become an important diagnostic tool for musculoskeletal diseases. Because of its wide availability in rheumatology practice, US has also been applied in other rheumatic diseases such ...as GCA. In acute GCA, US displays a non-compressible, hypoechoic, most commonly concentric arterial wall thickening. Temporal and axillary arteries should be examined in patients with suspected GCA and PMR. Additionally, almost all other large arteries, with the exception of the thoracic aorta, can be easily delineated by US. Many studies and several meta-analyses have been conducted to evaluate the diagnostic performance of US. US is more sensitive than temporal artery biopsy (TAB) because TAB evaluates only a limited anatomical region in a systemic disease. Most US studies arrive at specificities between 90 and 100% compared with the final clinical diagnosis. Reliability for reading US images and videos is excellent and comparable to reliability for reading TAB specimens. The advantage of US over other imaging techniques in GCA is its availability, safety and tolerability and its high resolution of 0.1 mm. Rheumatology departments are increasingly establishing fast-track clinics. Physicians can refer patients with suspected GCA within 24 h. Patients receive clinical and US examination by experienced specialists, establishing a clear diagnosis either before TAB or without the need for TAB. The introduction of fast-track clinics has led to a significant reduction of permanent vision loss. Furthermore, a process that primarily includes US is significantly more cost-effective than TAB.
Molecular alterations in malignant disease result in the expression or upregulations of various targets that can be used for imaging and treatment with radiopharmaceuticals. This theranostic ...principle has acquired greater importance in personalized medicine in recent years, particularly in oncology, where advanced tumors can be treated effectively with low side effects. Since the pioneering use of
I in differentiated thyroid cancer in the 1940s, remarkable achievements in nuclear medicine endoradiotherapy have been demonstrated, mainly in the treatment of neuroendocrine neoplasms by using
Lu-labeled somatostatin analogs or in the treatment of advanced prostate cancer using prostate-specific membrane antigen-directed radionuclide therapy. Besides that, this review focuses on promising novel radiopharmaceuticals and describes their preclinical and clinical status. Radiolabeled antibodies, such as
I-omburtamab directed against the B7-H3 protein on the surface of neuroblastoma cells; HuMab-5B1, a
Zr/
Lu-labeled antibody for the treatment of CA19-9-expressing malignancies; and
Lu-lilotomab, a CD37 antibody for the treatment of B-cell lymphomas, are being highlighted. The neurotensin receptor ligand
In/
Lu-3B-227 has demonstrated high potential in imaging and therapy for several malignancies (e.g., pancreatic adenocarcinomas). Targeting of the fibroblast activation protein is currently being explored for different tumor entities using PET imaging with the fibroblast activation protein inhibitor (FAPI)
Ga-FAPI-04, and the first therapeutic applications of
Y-FAPI-04 have been applied. After 2 decades of rapid development in theranostics, a variety of new targets are available for further clinical investigation.
To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated ...stereotactic radiotherapy (FSRT).
Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ≤-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an α/β ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model.
Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio OR 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068).
EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.
Prostate-specific membrane antigen (PSMA)-ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical ...trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.
We use the 100-member Max Planck Institute Grand Ensemble (MPI-GE) to disentangle the contributions from colocated dynamic atmospheric conditions and local thermodynamic effects of moisture ...limitation as drivers of variability in European summer heat extremes. Using a novel extreme event definition, we find that heat extremes with respect to the evolving mean climate increase by 70% under a moderate warming scenario during the twenty-first century. With a multiple regression approach, we find that the dynamical mechanisms representing blocking and anticyclonic conditions are the main driver of variability in extreme European summer temperatures, both in past and future climates. By contrast, local thermodynamic drivers play a secondary role in explaining the total variability in extreme temperatures. We also find that considering both dynamical and thermodynamical sources of variability simultaneously is crucial. Assessing only one type of drivers leads to an overestimation of their effect on extreme temperatures, particularly when considering only thermodynamical drivers. Lastly, we find that although most past and future heat extremes occur under favorable dynamical atmospheric conditions; this occurs 10–40% less frequently over Central Europe in the twenty-first century. By contrast, heat extremes over Central Europe occur 40% more frequently under concurrent extreme moisture limitation in the twenty-first Century. Our findings highlight a new type of neutral-atmosphere, moisture-driven heat extremes, and confirm that the increase in European heat extremes and associated variability increase are dominated by the local thermodynamic effect of moisture limitation.
Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following ...spinal cord point maximum doses (Dmax) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD22) Dmax ≤70 Gy; SBRT thecal sac EQD22 Dmax ≤25 Gy, thecal sac SBRT EQD22 Dmax to cumulative EQD22 Dmax ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.
Recent advances in research have greatly increased our understanding of the importance of the gut microbiota. Bacterial colonization of the intestine is critical to the normal development of many ...aspects of physiology such as the immune and endocrine systems. It is emerging that the influence of the gut microbiota also extends to modulation of host neural development. Furthermore, the overall balance in composition of the microbiota, together with the influence of pivotal species that induce specific responses, can modulate adult neural function, peripherally and centrally. Effects of commensal gut bacteria in adult animals include protection from the central effects of infection and inflammation as well as modulation of normal behavioral responses. There is now robust evidence that gut bacteria influence the enteric nervous system, an effect that may contribute to afferent signaling to the brain. The vagus nerve has also emerged as an important means of communicating signals from gut bacteria to the CNS. Further understanding of the mechanisms underlying microbiome–gut–brain communication will provide us with new insight into the symbiotic relationship between gut microbiota and their mammalian hosts and help us identify the potential for microbial-based therapeutic strategies to aid in the treatment of mood disorders.
To quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and ...to examine whether outcomes are affected by SBRT dosing regimen.
We identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy
vs >100 Gy
). Comparisons were made using log-rank testing.
Thirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, log-rank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy
(3-year local control 93%) than for those treated with BEDs of ≤100 Gy
(3-year local control 65%, P < .001).
Stereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy
are utilized.
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