927 research outputs found
NSA and DEA Intelligence Sharing: Why it is Legal and Why Reuters and the Good Wife Got it Wrong
The recent disclosures of secret U.S. government surveillance programs have brought to the forefront how intelligence agencies should manage the gathering and analysis of intelligence collected and when and how best to pass that information on to law enforcement. What is first collected for national security purposes can now potentially be used in a criminal trial. Law enforcement agents are said to utilize “parallel construction” to hide the original source that initiated the criminal investigation and develop their own evidence independent from this original source. Since the “wall” between intelligence agencies and law enforcement agencies fell down post-9/11 and intelligence information is now provided to law enforcement, should defendants have the right to review this evidence and are they entitled to this information (e.g. NSA wire intercepts) via discovery obligations? This article explores the constitutionality of “parallel construction,” the relationship between the intelligence community and law enforcement, and whether the non-disclosure of how a criminal investigation was initiated constitutes a violation of a defendant’s right to discovery pre-trial and right to a fair trial. Currently, Classified Information Procedures Act (CIPA) procedures are in place to protect against the disclosure of classified information while at the same time ensuring the defendant a right to a fair trial by having the judge in the case review the evidence ex parte and determine whether it should be disclosed to the defendant in redacted form (thereby fulfilling the prosecutor’s discovery obligations). This article argues that the procedures put in place, CIPA and Federal Rule of Criminal Procedure 16, adequately protect the defendant’s right to discovery and right to a fair trial, but public concerns as to law enforcement’s use of intelligence information, which bring to the forefront the consequences of intelligence sharing, are well founded and these intelligence sharing regulations should be narrower in scope
Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: A comparison to radiological progression
Background
The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation.
Methods
Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy.
Results
ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P \u3c 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15).
Conclusions
These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging
20 Years and 50 Issues
Comments of members/readers on what the Society and Mythlore have meant to them
Lumbar spine abnormalities and facet joint angles in asymptomatic elite junior tennis players
The prognostic impact of circulating tumour dna in melanoma patients treated with systemic therapies—beyond braf mutant detection
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen’s k = 0.798, p \u3c 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions
Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer
Objectives Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer.Methods All new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021.Results From July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046).Conclusions Early prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.<br/
DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo
Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern
Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration
Functional pluripotent characteristics have been observed in specific subpopulations of hepatic cells that express some of the known cholangiocyte markers. Although evidence indicates that specific cytokines, granulocyte-macrophage colony stimulating factors (GM-CSF) and stem cell factor (SCF) may be candidate treatments for liver injury, the role of these cytokines in intrahepatic biliary epithelium remodeling is unknown. Thus, our aim was to characterize the specific cytokines that regulate the remodeling potentials of cholangiocytes after 70% partial hepatectomy (PH). The expression of the cytokines and their downstream signaling molecules was studied in rats after 70% PH by immunoblots, and in small and large murine cholangiocyte cultures (SMCCs and LMCCs) by immunocytochemistry and real-time PCR. There was a significant and stable increase in SCF and GM-CSF levels until 7 days after PH. Real-time PCR analysis revealed significant increases of key remodeling molecules, such as S100A4 and miR-181b after SCF plus GM-CSF administration in SMCCs. SMCCs produced significant amounts of soluble and bound SCF and GM-CSF in response to TGF-β. When SMCCs were incubated with TGF-β plus anti–SCF and GM-CSF antibodies, there was a significant decrease in S100A4 expression. Furthermore, treatment of SMCCs with SCF + GM-CSF significantly increased matrix metalloproteinases (MMP-2 and MMP-9) mRNA as well as miR-181b expression along with a reduction of metalloproteinase inhibitor 3 (TIMP-3). The levels of MMP-2, MMP-9 and miR-181b were also up-regulated in rat liver and isolated cholangiocytes after PH
- …