Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Non-overweight depressed patients who respond to antidepressant treatment have a higher risk of later metabolic syndrome: findings from the METADAP cohort.

BACKGROUND: Major depressive disorder (MDD) is a complex disorder with a significant public health burden. Depression remission is often associated with weight gain, a major risk factor for metabolic syndrome (MetS). The primary objective of our study was to assess prospectively the impact of response to antidepressant treatment on developing MetS in a sample of MDD patients with a current major depressive episode (MDE) and who are newly initiating their treatment. METHODS: In the 6-month prospective METADAP cohort, non-overweight patients, body mass index <25 kg/m2, with MDD and a current MDE were assessed for treatment response after 3 months of treatment, and incidence of MetS after 3 and 6 months of treatment. Outcome variables were MetS, number of MetS criteria, and each MetS criterion (high waist circumference, high blood pressure, high triglyceridemia, low high-density lipoprotein-cholesterolemia, and high fasting plasma glucose). RESULTS: In total, 98/169 patients (58%) responded to treatment after 3 months. A total of 2.7% (1/38) developed MetS out of which 12.7% (10/79) (p value < 0.001) had responded to treatment after 3 months. The fixed-effect regression models showed that those who responded to treatment after 3 months of follow-up had an 8.6 times higher odds of developing MetS (odds ratio = 8.58, 95% confidence interval 3.89-18.93, p value < 0.001). CONCLUSION: Compared to non-responders, non-overweight patients who responded to treatment after 3 months of antidepressant treatment had a significantly higher risk of developing MetS during the 6 months of treatment. Psychiatrists and nurses should closely monitor the metabolic profile of their patients, especially those who respond to treatment.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study.

BACKGROUND: Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment. METHODS: A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response. RESULTS: Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) -0.084 to -0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58-536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002-0.0067; p = 0.03). CONCLUSIONS: Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

Reviving through human hippocampal newborn neurons.

Recent contradictory data has renewed discussion regarding the existence of adult hippocampal neurogenesis (AHN) in humans, i.e., the continued production of new neurons in the brain after birth. The present review revisits the debate of AHN in humans from a historical point of view in the face of contradictory evidence, analyzing the methods employed to investigate this phenomenon. Thus, to date, of the 57 studies performed in humans that we reviewed, 84% (48) concluded in favor of the presence of newborn neurons in the human adult hippocampus. Besides quality of the tissue (such as postmortem intervals below 26hours as well as tissue conservation and fixation), considerations for assessing and quantify AHN in the human brain require the use of stereology and toxicological analyses of clinical data of the patient.

PPAR-γ Agonists for the Treatment of Major Depression: A Review.

Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

Comparison of tritiated-water standards by liquid scintillation for calibration of a new Standard Reference Material®.

A new National Institute of Standards and Technology (NIST) tritiated-water ((3)H-labeled oxidane) standard was prepared and calibrated. It is the 17th in a series of linked standards since 1954 and will be disseminated as Standard Reference Material® SRM 4927G, having a massic activity of 544.2kBqg(-1), with an expanded (k=2) relative standard uncertainty of 0.96%, at a Reference Time of 1200 EST, 1 May 2015. The calibration is based on relative liquid scintillation (LS) measurements using quench-varied efficiency tracing with two previous 1999 issues, viz., SRM 4927F and 4926E. Measurement comparisons were also made with respect to a 1994 tritiated-water French national standard and to a tritiated-water solution measured by 19 laboratories as part of an international measurement comparison organized by the Bureau International des Poids et Mesures (BIPM) in 2009. Confirmatory measurements for the massic activity of both SRM 4927F and 4927G by a triple-to-double coincidence ratio (TDCR) technique were also made.

[Vortioxetine: a new antidepressant to treat depressive episodes]. / La vortioxétine : un nouvel antidépresseur pour traiter les épisodes dépressifs caractérisés.

Vortioxetine is a new antidepressant, which mechanism of action is multimodal, targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin transporter (5-HTT). Its efficacy and safety were assessed in fourteen studies including more than 3700 patients with a major depressive episode and treated with vortioxetine. In short-term studies (8 weeks), vortioxetine is more efficacious than placebo in decreasing depressive symptoms as measured by the MADRS total score, response rate (vortioxetine: 53.2% vs placebo: 35.2%) and remission rate (vortioxetine: 29.2% vs placebo: 19.3%). In a long-term study (52 weeks), vortioxetine is also superior to placebo in preventing relapses and recurrences. Moreover, in second line treatment, after failure of a first line selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrin reuptake inhibitor (SNRI), vortioxetine is superior to agomelatine in improving depressive symptoms and achieving response and remission. Furthermore, the positive effects of vortioxetine on improvement of cognitive symptoms of major depressive episodes are particularly well established in several clinical trials. The tolerability profile of vortioxetine is favourable. The recommended daily posology of vortioxetine is 10mg/d. Vortioxetine is a new antidepressant drug with a multimodal mechanism of action, well-documented efficacy and safety profiles.

[The use of therapeutic apheresis in neurological diseases and comparison between plasma exchange and immunoadsorption]. / Utilizzo dell'aferesi terapeutica in corso di patologie neurologiche comparazione tra plasmaexchange ed immunoadsorbimento.

The use of plasmapheresis in neurological diseases with immune-mediated pathogenesis is widely certified. In recent years, the technological evolution of the dialysis membranes allowed to accompany the classical plasma exchange (PEX) treatment of apheresis by means of selective adsorption (IA). It has proved to be of equal therapeutic efficacy and, at the same time, devoid of most of the PEX side effects. The recent guidelines of the American Society for Apheresis (ASFA) and, later, the American Academy of Neurology, outlined directions and diagrams for the application of the method that has found wide use in many neurological diseases on the basis of auto-antibodies; in particular in Myasthenia Gravis, Guillain-Barre Syndrome, Multiple Sclerosis and Chronic Demyelinating Polyradiculoneuropathy. We add our experience in the treatment of 13 patients suffering from Myasthenia Gravis, treated over a four years period with filters containing tryptophan immunoadsorption in polyvinyl alcohol gel. The results confirm the achievement of a rapid regression of clinical symptoms, together with the rapid fall in the levels of antibody against acetylcholine-receptor. Therefore, the method of AI is to be considered of equal therapeutic efficacy of PEX, providing greater security in its use.

Development of an Ultra-Pure, Carrier-Free (209)Po Solution Standard.

Ultra-pure, carrier-free (209)Po solution standards have been prepared and standardized for their massic alpha-particle emission rate. The standards, which will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material SRM 4326a, have a mean mass of (5.169 ± 0.003) g of a solution of polonium in nominal 2.0 mol▪L(-1) HCl (having a solution density of (1.032 ± 0.002) g▪ mL(-1) at 20 °C) that are contained in 5 mL, flame-sealed, borosilicate glass ampoules. They are certified to contain a (209)Po massic alpha-particle emission rate of (39.01 ± 0.18) s(-1)▪g(-1) as of a reference time of 1200 EST, 01 December 2013. This new standard series replaces SRM 4326 that was issued by NIST in 1994. The standardization was based on 4πα liquid scintillation (LS) spectrometry with two different LS counting systems and under wide variations in measurement and counting source conditions. The methodology for the standardization, with corrections for detection of the low-energy conversion electrons from the delayed 2 keV isomeric state in (205)Pb and for the radiations accompanying the small 0.45 % electron-capture branch to (209)Bi, involves a unique spectral analysis procedure that is specific for the case of (209)Po decay. The entire measurement protocol is similar, but revised and improved from that used for SRM 4326. Spectroscopic impurity analyses revealed that no photon-emitting or alpha-emitting radionuclidic impurities were detected. The most common impurity associated with (209)Po is (208)Po and the activity ratio of (208)Po/(209)Po was < 10(-7).

Standardization of ²³7Np.

The standardization of (237)Np was investigated. The certified massic activity for (237)Np was obtained by 4παß liquid scintillation (LS) counting with correction for the (233)Pa daughter using the CIEMAT/NIST efficiency tracing method using a (3)H standard. Confirmatory measurements were also performed by high-resolution HPGe gamma-ray spectrometry, and by 4παß(LS)-γ(NaI) anticoincidence counting. All results agree within the respective method's uncertainties. It was confirmed that the (237)Np/(233)Pa radioactive equilibrium is disturbed when making dilutions and/or removing aliquots.

100 years of radionuclide metrology.

The discipline of radionuclide metrology at national standards institutes started in 1913 with the certification by Curie, Rutherford and Meyer of the first primary standards of radium. In early years, radium was a valuable commodity and the aim of the standards was largely to facilitate trade. The focus later changed to providing standards for the new wide range of radionuclides, so that radioactivity could be used for healthcare and industrial applications while minimising the risk to patients, workers and the environment. National measurement institutes responded to the changing demands by developing new techniques for realising primary standards of radioactivity. Looking ahead, there are likely to be demands for standards for new radionuclides used in nuclear medicine, an expansion of the scope of the field into quantitative imaging to facilitate accurate patient dosimetry for nuclear medicine, and an increasing need for accurate standards for radioactive waste management and nuclear forensics.

A novel application for 222Rn emanation standards: radon-cryptophane host chemistry.

In collaboration with the University of Pennsylvania, a (222)Rn emanation source was used for the determination of the binding affinity of radon to a cryptophane molecular host. This source was similar to a (222)Rn emanation standard that was developed and disseminated by the National Institute of Standards and Technology (NIST). The novel experimental design involved performing the reactions at femtomole levels, developing exacting gravimetric sampling methods and making precise (222)Rn assays by liquid scintillation counting. A cryptophane-radon association constant was determined, K(A)=(49,000±12,000) L mol(-1) at 293 K, which was the first measurement of radon binding to a molecular host.

A new primary standardization of 229Th.

The National Institute of Standards and Technology (NIST) has certified a high-purity (229)Th Standard Reference Material as SRM 4328C, based on live-timed 4pialphabeta-gamma anticoincidence counting (LTAC) of the equilibrium solution. The LTAC system was optimized to minimize the uncertainty in the result due to the two short-lived ground-states present in the decay chain. Confirmatory measurements were carried out by four other methods. Furthermore, the present absolute activity and measured gamma-ray emission rates were combined to obtain gamma-ray emission probabilities.

Investigation into the standardization of 99Tc.

The standardization of (99)Tc by several primary methods was investigated. This was performed to support a new (99)Tc transfer standard that has been developed and will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material SRM 4288B. The standardization for the (99)Tc content of the solution was based on 4pibeta liquid scintillation (LS) measurements with (3)H-standard efficiency tracing (CIEMAT/NIST method). Confirmatory determinations were performed by 4pibeta(LS)-gamma(NaI) live-timed anti-coincidence (LTAC) counting and an LS-based 4pibeta triple-to-double coincidence ratio (TDCR) method.

Asthma induced by inhalation of flour in adults with food allergy to wheat.

BACKGROUND: Wheat is one of the major food allergens and it is also an inhalant allergen in workers exposed to flour dusts. Food allergy to wheat in adulthood seems to be rare and has never been reported to be associated with asthma induced by flour inhalation. OBJECTIVE: The study aimed at detecting adults with food allergy to wheat and screening them for the presence of specific bronchial reactivity to inhaled wheat proteins. METHODS: Adults with a history of adverse reactions to ingestion of wheat underwent skin prick test with commercial wheat extract and were assessed for the presence of specific wheat IgE in the sera. Food sensitivity to wheat was confirmed by double-blind, placebo-controlled food challenge (DBPCFC). Specific bronchial reactivity was investigated through a specific bronchial challenge with wheat proteins. RESULTS: In nine patients with evidence of specific IgE response to wheat, a diagnosis of food allergy was made by DBPCFC. Only two subjects had asthma as disease induced by ingestion of wheat. Seven subjects reported a history of respiratory symptoms when exposed to flour dusts. A significant reduction of forced expiratory volume in 1 s (FEV(1)) was detected in these seven patients when a specific bronchial challenge with flour proteins was performed. Only three out of seven subjects with asthma induced by flour could be considered occupationally exposed to flour dusts. CONCLUSION: For the first time, it has been shown that specific bronchial reactivity to wheat proteins can be detected in patients with different disorders associated with food allergy to wheat. The presence of asthma induced by inhaled flour is not strictly related to occupational exposure and it may also occur in subjects not displaying asthma among symptoms induced by wheat ingestion.

63Ni, its half-life and standardization: revisited.

Recent liquid scintillation (LS) measurements at the National Institute of Standards and Technology (NIST) and at the Laboratoire National Henri Becquerel (LNHB) on a standardized (63)Ni solution that has been tracked for nearly 40 years have resulted in several important findings: (i) a (63)Ni half-life value of 101.2 +/- 1.5 a has been determined with the present decay data. This value is consistent with a previous specific activity determination and with an earlier value from decay measurements; and it appears to be more satisfactory than a recent data evaluator's recommended value of 98.7 a. (ii) All solution standards of (63)Ni as disseminated by NIST for the past 38(+) years are internally consistent with past and recent standardizations. (iii) Primary LS standardizations of (63)Ni by the triple-to-double coincidence ratio (TDCR) method and by CIEMAT/NIST (3)H-standard efficiency tracing (CNET) appear to be comparable, although the latter methodology is believed to be inherently inferior. (iv) There is excellent measurement agreement between NIST and LNHB for (63)Ni primary standardizations.

A liquid-scintillation-based primary standardization of 210Pb.

A new radioactivity solution standard of 210Pb has been developed and will be disseminated by the National Institute of Standards and Technology (NIST) as standard reference material (SRM) 4337. This new 210Pb solution standard is contained in a 5 mL flame-sealed borosilicate glass ampoule, consists of (5.133+/-0.002)g of a nominal 1mol L(-1) nitric acid solution, has a density of (1.028+/-0.002)g mL(-1) at 20 degrees C, has carrier ion concentrations of about 11 microg Pb2+ and 21 microg Bi3+ per gram of solution, and is certified to contain a massic activity (9.037+/-0.22)kBq g(-1) as of the reference time 1200 EST, 15 June 2006. All of the uncertainties cited above correspond to standard uncertainties multiplied by a coverage factor k=2. The standardization for the (210)Pb content of the solution was based on 4pialphabeta liquid scintillation (LS) measurements using CIEMAT/NIST (3)H-standard efficiency tracing (CNET). Confirmatory determinations were also performed by high-resolution HPGe gamma-ray spectrometry, by 2pialpha spectrometry with a Si surface barrier detector of separated 210Po, and by 4pibeta(LS)-gamma(NaI) anticoincidence counting.

PON1 activity and genotype in patients with arterial ischemic stroke and in healthy individuals.

OBJECTIVE: Paraoxonase-1 (PON1) is an esterase with antioxidant properties. Low PON1 enzyme activity or specific allelic polymorphisms seem to be associated with the risk of developing coronary artery disease or acute ischemic stroke (AIS). Our objective was to determine the distribution of both PON1 enzyme activity and its genotype in a group of patients with AIS. MATERIALS AND METHODS: PON1 activity and the relative Q192R and L55M polymorphisms in the PON1 gene were assessed on 126 survivors of a first AIS and in 92 healthy subjects. RESULTS: The genotype distribution for PON1 Q192R and L55M polymorphisms was similar in AIS patients and healthy subjects, but patients carrying the QRLL or RRLL genotype combination had lower PON1 enzyme activity compared with healthy subjects with the same genotype. CONCLUSION: We postulate that lower than expected PON1 enzyme activity within specific genotypes might explain the reported association between R and L alleles and the risk of developing AIS.

A note on the half-life of 209Po.

The widely adopted value of (102+/-5)a for the (209)Po half-life, which is based on a single determination reported in 1956, appears to be in error by a large factor. Decay data from two separate primary standardizations of a (209)Po solution standard, conducted approximately 12 years apart, are inconsistent with the adopted value and its assigned uncertainty. An estimated half-life, larger than the adopted value by about 25%, is more consistent with the standardization data. A longer half-life is also supported by measurements on a recently standardized (210)Pb solution standard.

Serum levels of carbamazepine and cortical excitability by magnetic brain stimulation.

We investigated the correlation between serum levels of carbamazepine (CBZ) and motor excitability studied by different parameters of transcranial magnetic stimulation (TMS) in patients at the beginning of antiepileptic treatment. A total of 10 patients with complex partial seizures following stroke were treated with loading doses of CBZ. Motor evoked potential (MEP) was recorded from the thenar eminence (TE) muscles of the unaffected arm. In all patients, we studied rest and active motor threshold (rMT, aMT), MEP amplitude and cortical silent period (CSP). In three patients, intracortical inhibition (ICI) and intracortical facilitation (ICF) were measured using paired TMS at short interstimulus intervals (1-25 ms). The recording sessions were performed before treatment and after 7, 15 and 60 days (SD=16 days). Serum level of CBZ were monitored at each recording session. We observed a progressive increase in rMT and aMT until the serum levels of CBZ reached a steady state condition. No significant changes were observed in MEP amplitude, CSP, ICI and ICF. This study documents the increase of both motor threshold and drug serum levels in patients treated with loading doses of CBZ, suggesting a relationship between drug metabolism and the effect on motor cortical excitability.