Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination.

Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.

Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice.

We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE(-/-)Fbn1(C1039G+/-)) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood-cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE(-/-) (n=61) and ApoE(-/-)Fbn1(C1039G+/-) (n=73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoE(-/-)Fbn1(C1039G+/-) mice compared to age-matched ApoE(-/-) mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-ß, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoE(-/-)Fbn1(C1039G+/-) mice showed xanthomas in the brain, compared to 23% of their ApoE(-/-) littermates. Xanthomas were mainly located in fibrillin-1-rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas.

Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging.

RATIONALE: One of the key targets of psychopharmacology research is to determine the potential sites of action of antidepressants in order to characterise their underlying mechanism of action. OBJECTIVE: Using blood oxygenation level-dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), the neuroanatomical target-sites of reboxetine (a selective noradrenaline reuptake inhibitor) and bupropion (an antidepressant with stimulatory effects on dopamine and potentially on noradrenaline) were mapped. METHODS: Separate groups of rats were challenged acutely or chronically (daily injections for 14 days) with saline or psychoactive compounds and scanned. Subsequent statistical parametric mapping of the main effects of the drug was performed by identifying changes in the BOLD signal. RESULTS: Acute reboxetine challenge at a low dose (10 mg/kg i.p.) produced positive BOLD responses specifically in the hypothalamus, whereas a larger dose (30 mg/kg i.p.) produced activations in the hypothalamus, anterior hippocampus and prefrontal cortex. Chronic reboxetine (30 mg/kg i.p.) treatment induced increased BOLD responses in the posterior hippocampus and prefrontal cortex, while no significant contrast changes were observed in the hypothalamus and a significant decrease was apparent in the amygdala. In contrast, acute bupropion (15 and 30 mg/kg i.p.) challenge in both doses produced no significant contrast changes in the regions of interest. However, chronic bupropion treatment (30 mg/kg i.p.) produced robust increases in BOLD responses in the hippocampus, amygdala and prefrontal cortex. CONCLUSION: In summary, this study demonstrates that reboxetine and bupropion evoke a significant increase in BOLD functional activity in specific regions of the brain, including the hypothalamus, hippocampus, prefrontal cortex and amygdala. Furthermore, the study illustrates the potential value of pharmacological MRI in rodents to delineate pharmacologically induced changes in regional brain function.

Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging.

RATIONALE: The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS. OBJECTIVE: Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT(1A) receptors, citalopram was co-administered with a highly selective 5-HT(1A) receptor antagonist WAY100635. RESULTS: Acute citalopram treatment (10 and 20 mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14 days of chronic daily administration of citalopram (20 mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3 mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures. CONCLUSION: The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.

Overexpression of human wildtype torsinA and human DeltaGAG torsinA in a transgenic mouse model causes phenotypic abnormalities.

Primary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors must contribute to the factual manifestation of the disease. We generated 4 independent transgenic mouse lines, two overexpressing human mutant torsinA and two overexpressing human wildtype torsinA using a strong murine prion protein promoter. Our data provide for the first time in vivo evidence that not only mutant torsinA is detrimental to neuronal cells but that also wildtype torsinA can lead to neuronal dysfunction when overexpressed at high levels. This hypothesis is supported by (i) neuropathological findings, (ii) neurochemistry, (iii) behavioral abnormalities and (iv) DTI-MRI analysis.

Changing body temperature affects the T2* signal in the rat brain and reveals hypothalamic activity.

This study was designed to determine brain activity in the hypothalamus-in particular the thermoregulatory function of the hypothalamic preoptic area (PO). We experimentally changed the body temperature in rats within the physiological range (37-39 degrees C) and monitored changes in blood oxygenation level-dependent (BOLD) MR signal. To explore PO activity we had to deal with general signal changes caused by temperature-dependent alterations in the affinity of oxygen for hemoglobin, which contributes to BOLD contrast because it is partly sensitive to the amount of paramagnetic deoxyhemoglobin in the voxel. To reduce these overall temperature-induced effects, we corrected the BOLD data using brain-specific correction algorithms. The results showed activity of the PO during body warming from 38 degrees C to 39 degrees C, supported by an increased BOLD signal after correction. This is the first fMRI study on the autonomous nervous system in which hypothalamic activity elicited by changes in the internal environment (body temperature) was monitored. In this study we also demonstrate 1) that any fMRI study of anesthetized small animals should guard against background BOLD signal drift, since animals are vulnerable to body temperature fluctuations; and 2) the existence of a link between PO activity and the sympathetically-mediated opening of the arteriovenous anastomoses in a parallel study on the rat tail, a peripheral thermoregulatory organ.

Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease.

Transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP[V717I]) in neurons develop amyloid plaques in the brain, thus demonstrating the most prominent neuropathological hallmark of Alzheimer's disease. In vivo 3D T2*-weighted MRI on these mice (24 months of age) revealed hypointense brain inclusions that affected the thalamus almost exclusively. Upon correlating these MRI observations with a panel of different histologic staining techniques, it appeared that only plaques that were positive for both thioflavin-S and iron were visible on the MR images. Numerous thioflavin-S-positive plaques in the cortex that did not display iron staining remained invisible to MRI. The in vivo detection of amyloid plaques in this mouse model, using the intrinsic MRI contrast arising from the iron associated with the plaques, creates an unexpected opportunity for the noninvasive investigation of the longitudinal development of the plaques in the same animal. Thus, this work provides further research opportunities for analyzing younger APP[V717I] mouse models with the knowledge of the final outcome at 24 months of age.

In-vivo non-invasive study of the thermoregulatory function of the blood vessels in the rat tail using magnetic resonance angiography.

In rats, a significant portion of total body heat loss occurs through sympathetically mediated changes in tail blood flow, making the rat tail a convenient model to study vasomotor activity during thermoregulation. Our aim was to perform a non-invasive study of the mechanisms of blood vessel control in the rat tail upon increasing body temperature. In anaesthetized rats, blood vessel temperature was monitored using non-invasive thermistors positioned on the skin surface, covering the ventral artery (Ta) and lateral vein (Tv), and changes in blood vessel size were measured using in-vivo magnetic resonance angiography (MRA). Two important regions of the tail (base and middle) were studied during a gradual rise of rectal temperature (Tr) from 37 to 40 degrees C. MRA data show that increasing Tr causes increased diameter of both arteries and veins of the tail, that venous diameter changes are greater than arterial diameter changes, and that diameter changes of both types of vessel are greater at the base of the tail than in the middle. Temperature data allowed calculation of (Ta - Tv), which we used as an index of flow through arteriovenous anastomoses (AVAs). The data suggest that AVAs near the base of the tail are important in heat exchange, and that they remain open only for Tr values between 38 and 39 degrees C.

Lipoprotein abnormalities in chronic haemodialysis patients.

Measurement of lipids, apolipoproteins A-I, A-II, B, C-III, Lp(a) and cholesterol, phospholipids, apo C-III in lipoprotein with and without apolipoprotein B was made in 49 patients (18 women and 31 men; mean age 50 +/- 15 years) undergoing maintenance haemodialysis for chronic renal failure. A group of 49 healthy people, matched for sex and age, acted as controls. In the haemodialysis group, special attention was placed upon the comparison of patients who had evident cardiovascular alterations (n = 17) with the residual group (n = 32). The concentration of apo C-III in apolipoprotein B containing lipoproteins was statistically higher in the patients with arterial disease than in the remaining subjects, whereas the ratio apo C-III from Lp no B/apo C-III from Lp B was decreased. Compared to controls, haemodialysis patients had significantly higher values of triglycerides, apolipoproteins C-III, Lp(a), and apolipoprotein C-III from apolipoprotein B-containing lipoproteins (LpB); in contrast, concentrations of phospholipids and cholesterol from lipoproteins without apolipoprotein B (Lp no B) and apolipoprotein A-II were significantly reduced in patients. Discriminant analysis indicated that the levels of apolipoprotein C-III and apolipoprotein C-III from LpB were the best indicators of deranged lipid transport in patients with chronic renal failure. Our data suggest that chronic haemodialysis patients tend to exhibit qualitative abnormalities of serum apolipoprotein-B triglyceride rich particles containing apolipoprotein C-III or (a).

[Assay of serum apolipoprotein A-II by electro-immunodiffusion on ready-for-use plates. Clinical applications]. / Dosage de l'apolipoprotéine A-II sérique par électro-immunodiffusion sur plaques prêtes à l'emploi. Applications cliniques.

Few papers have been devoted to the study of apolipoprotein A-II (apo A-II), one of the major peptides contained in HDL, probably because of the methodological difficulties associated with its assay. The aim of this study is to provide the clinical biochemist with a simply easy to use assay technique. We have been able to demonstrate the practical value of apo A-II assay in hepatology and in the detection of excessive drinkers. On the other hand, our results indicate that apo A-II is not a parameter of choice for the detection of coronary atherosclerosis.

[Methods of biochemical analysis in hyperliproproteinemias]. / Méthodes d'exploration biochimique des hyperlipoprotéinémies.

In the past years, the structure and function of the plasma lipoproteins and apolipoproteins have been elucidated. The biochemical defect of several genetic lipoprotein disorders and their role in the development of atherosclerosis are now well understood. Electrophoretic separation of lipoproteins in polyacrylamide gradient gel gives an acurate characterization of the different lipoproteins and allows the phenotyping of hyperlipoproteinemia. Abnormal concentrations of plasma lipoproteins have been known for many years to be a major risk factor in the development of premature ischemic heart disease. Although large-scale epidemiological studies have focused attention on the association between above-normal concentrations of plasma lipids and coronary atherosclerosis, recent findings have shown that quantitative lipoprotein and apoprotein determination may be a more nearly accurate predictor in the recognition of atherosclerosis. The risk for vascular disease seems to be particularly associated with an increase in the concentrations of apolipoprotein B (apo B), the major protein moiety of low density lipoproteins and a decrease in apolipoprotein Al, the major polypeptide of high-density lipoproteins.

Is blood pressure variability related to activity of the sympathetic system?

1. In 70 patients with untreated essential hypertension, blood pressure variability was correlated to plasma catecholamines and to the response of blood pressure and peripheral flow to cold pressure and handgrip tests. 2. Supine blood pressure was recorded every 5 min, during 3 h. Variability was defined as the standard deviation of the mean of the readings in that period. 3. Blood pressure variability is positively and significantly correlated to the level of pressure and to age. 4. No significant correlation could be found with plasma catecholamines and sympathetic function tests. 5. It is concluded that blood pressure variability is related to the level of pressure but not to activity of the sympathetic nerves.

[Purification and characterization of protease inhibitors from urine during pregnancy (author's transl)]. / Purification et caracterisation des inhibiteurs de protéases de l'urine humaine.

Two forms of urinary trypsin inhibitor, A and B, were purified from the pooled urine from pregnant women using non-denaturing methods. The inhibitor B arose from the inhibitor A and was not present in native urine. Electrophoresis on polyacrylamide gel in the presence of sodium dodecyl sulfate indicated a new heterogeneity of the inhibitor B with molecular weights of 33 000 and 24 000; the molecular weight obtained for the inhibitor A was 50 000. Inhibitors A and B were acidic proteins with an isoelectric pH of about 2.6 for A and about 4.2 for B. Inhibitor A and inter-alpha-trypsin inhibitor formed a precipitate with an antiserum to purified inhibitor B. But neither inhibitor A nor inhibitor B formed a precipitate with anti whole human serum or anti-inter-alpha-trypsin inhibitor antiserum. Measurements of specific activity of inhibitor A were consistent with two active sites in the molecule.