Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of ...circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes.
We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans.
Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response EMR) and a 2.5-log decrease after two cycles (major molecular response MMR) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival.
Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.
Learning a new motor task modifies feedforward (i.e., voluntary) motor commands and such learning also changes the sensitivity of feedback responses (i.e., reflexes) to mechanical perturbations 1–9. ...For example, after people learn to generate straight reaching movements in the presence of an external force field or learn to reduce shoulder muscle activity when generating pure elbow movements with shoulder fixation, evoked stretch reflex responses to mechanical perturbations reflect the learning expressed during self-initiated reaching. Such a transfer from feedforward motor commands to feedback responses is thought to take place because of shared neural circuits at the level of the spinal cord, brainstem, and cerebral cortex 10–13. The presence of shared neural resources also predicts the transfer from feedback responses to feedforward motor commands. Little is known about such a transfer presumably because it is relatively hard to elicit learning in reflexes without engaging associated voluntary responses following mechanical perturbations. Here, we demonstrate such transfer by leveraging two approaches to elicit stretch reflexes while minimizing engagement of voluntary motor responses in the learning process: applying very short mechanical perturbations 14–19 and instructing participants to not respond to them 20–26. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer.
•Long-latency stretch reflex responses can learn altered arm dynamics•This learning occurs with minimal engagement of voluntary motor responses•What reflex responses learn transfers to voluntary motor commands
Maeda et al. show that feedback responses to mechanical perturbations change appropriately when the mechanical properties of the arm are altered and that such changes transfer to the feedforward control of reaching. This finding furthers the notion that feedback and feedforward control processes share common neural circuits.
Tumor markers can facilitate understanding molecular cell biology of neoplasia and provide potential targets for the diagnosis and insight for intervention. We here identify a novel murine gene, ...hepcarcin (hcn), encoding a 7-kb mRNA-like transcript. The gene appears to be the murine ortholog of the human alpha gene, that is, MALAT-1. The gene and homologs lack credible open reading frames, consistent with a highly conserved large noncoding RNA (ncRNA). In all nodules of procarcinogen-induced murine hepatocellular carcinomas (HCCs) and human HCCs, expression was markedly elevated compared to the uninvolved liver. Quantitative analyses indicated a 6-7-fold increased RNA level in HCCs versus uninvolved liver, advancing this as a molecule of interest. This ncRNA was overexpressed in all five non-hepatic human carcinomas analysed, consistent with a potential marker for neoplastic cells and potential participant in the molecular cell biology of neoplasia.
Abstract
The β
2
adrenergic receptor (β
2
AR) signals through both G
s
and G
i
in cardiac myocytes, and the G
i
pathway counteracts the G
s
pathway. However, G
i
coupling is much less efficient than ...G
s
coupling in most cell-based and biochemical assays, making it difficult to study β
2
AR−G
i
interactions. Here we investigate the role of phospholipid composition on G
s
and G
i
coupling. While negatively charged phospholipids are known to enhance agonist affinity and stabilize an active state of the β
2
AR, we find that they impair coupling to G
i3
and facilitate coupling to G
s
. Positively charged Ca
2+
and Mg
2+
, known to interact with the negative charge on phospholipids, facilitates G
i3
coupling. Mutational analysis suggests that Ca
2+
coordinates an interaction between phospholipid and the negatively charged EDGE motif on the amino terminal helix of G
i3
. Taken together, our observations suggest that local membrane charge modulates the interaction between β
2
AR and competing G protein subtypes.
MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.
Using ...MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.
Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range IQR = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).
MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -
Recent work has shown that, when countering external forces, the nervous system adjusts not only predictive (i.e., feedforward) control of reaching but also reflex (i.e., feedback) responses to ...mechanical perturbations. Here we show that altering the physical properties of the arm (i.e., intersegmental dynamics) causes the nervous system to adjust feedforward control and that this learning transfers to feedback responses even though the latter were never directly trained. Forty-five human participants (30 females) performed a single-joint elbow reaching task and countered mechanical perturbations that created pure elbow motion. In our first experiment, we altered intersegmental dynamics by asking participants to generate pure elbow movements when the shoulder joint was either free to rotate or locked by the robotic manipulandum. With the shoulder unlocked, we found robust activation of shoulder flexor muscles for pure elbow flexion trials, as required to counter the interaction torques that arise at the shoulder because of forearm rotation. After locking the shoulder joint, which cancels these interaction torques, we found a substantial reduction in shoulder muscle activity over many trials. In our second experiment, we tested whether such learning transfers to feedback control. Mechanical perturbations applied to the arm with the shoulder unlocked revealed that feedback responses also account for intersegmental dynamics. After locking the shoulder joint, we found a substantial reduction in shoulder feedback responses, as appropriate for the altered intersegmental dynamics. Our work suggests that feedforward and feedback control share an internal model of the arm's dynamics.
Here we show that altering the physical properties of the arm causes people to learn new motor commands and that this learning transfers to their reflex responses to unexpected mechanical perturbations, even though the reflex responses were never directly trained. Our results suggest that feedforward motor commands and reflex responses share an internal model of the arm's dynamics.
Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology ...underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.
Self-Walking Gel Maeda, S.; Hara, Y.; Sakai, T. ...
Advanced materials (Weinheim),
11/2007, Letnik:
19, Številka:
21
Journal Article
Recenzirano
You'll never walk alone? A gel actuator that can generate autonomous motility with a wormlike motion without external driving stimuli is produced. The autonomous motion is produced by dissipating the ...chemical energy of an oscillating reaction occurring inside the gel. Even though the gel is completely composed of synthetic polymer, it shows an autonomous motion as if it were “alive”. By coupling this with a ratchet mechanism, the gel walks by repeatedly bending and stretching itself like a looper (see figure).
Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a ...thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements.
We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements.
CPB time, post-bypass rotational thromboelastometry (ROTEM®) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg−1, P<0.001) and packed red cell transfusion requirement (11 vs 23 ml kg−1, P=0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P=0.014).
Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients.
UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011).
Tumor-associated macrophages are abundant infiltrating cells in the tumor microenvironment (TME). Macrophages can be classified into several types of subsets based on their immune responses. Among ...those subsets, M2 macrophages contribute to anti-inflammatory responses and create an immunosuppressive environment that promotes tumor cell proliferation. In a previous study, human cancer patients with high M2 macrophages showed a worse prognosis for many types of tumors. However, studies examining the relationship between M2 macrophages and clinical outcomes in canine tumors are limited. In the previous human and canine studies, CD204 has been used as the marker for detecting M2 macrophages. Then we evaluated CD204+ and total macrophages infiltration and its association with clinical outcomes in canine solid tumors. In this study, we examined dogs with oral malignant melanoma (OMM), pulmonary adenocarcinoma (PA), hepatocellular carcinoma (HCC), and transitional cell carcinoma (TCC). Compared to healthy tissues, CD204+ and total macrophages were increased in OMM, PA, and TCC, but not in HCC. High CD204+ macrophage levels were significantly associated with lung metastasis in TCC (P = 0.030). Kaplan-Meier analysis revealed that high CD204+ macrophage levels were associated with shorter overall survival (OS) in canine patients with PA (P = 0.012) and TCC (P = 0.0053). These results suggest that CD204+ macrophages contribute to tumor progression and could be a prognostic factor in dogs with PA and TCC.
•CD204+ and Iba-1+ macrophages were evaluated in 4 types of canine solid tumors.•CD204+ macrophages may be a prognostic factor in canine lung and bladder cancer.•Iba-1+ macrophages were not associated with prognosis in canine cancers.
PDF
