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Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805.

Veel ouders zullen weleens een dag hebben waarop ze oplopen tegen emotionele uitputting, emotionele afstand voelen tot hun kinderen en ze het gevoel hebben dat ze genoeg hebben van het ouderschap. Maar sommige ouders ervaren deze kenmerken in een ernstige mate, en dan is er sprake van een gezondheidsprobleem dat ‘ouderlijke burn-out’ wordt genoemd. Een ouderlijke burn-out ontstaat wanneer ouders chronisch gebukt gaan onder ernstige stress, zonder over voldoende externe en interne hulpbronnen te beschikken (in het vervolg kortweg aangeduid met ‘hulpbronnen’, red.) voor het omgaan daarmee, wat behalve voor de ouder zelf ook tot ongunstige gevolgen kan leiden voor de partner (relatieconflicten bijvoorbeeld) en de kinderen (verwaarlozing en geweld). Het is echter nog niet duidelijk hoe de interacties tussen die problemen er precies uitzien, hoe het ene kenmerk het andere na verloop van tijd uitlokt (zodat ze potentieel steeds ernstiger worden), en hoe deze kenmerken worden beïnvloed door de dagelijkse veranderingen in de gezinscontext. Daarom hebben we voor dit onderzoek een steekproef van vijftig ouders geworven (de hoofdanalyses gingen over 43 moeders met een mede-ouder, de sensitiviteitsanalyses over de hele steekproef) uit de algemene bevolking, met de bedoeling een beeld te krijgen van de hoofdkenmerken van ouderlijke burn-out en de gezinscontext, dagelijks gedurende 56 dagen. Voor het genereren van de netwerkmodellen hebben we Multilevel Vector Autoregressieve modellen gebruikt (mIVAR). De resultaten laten zien dat uitputting bijdraagt aan ouderlijke burn-out: het voorspelt zichzelf en hangt nauw samen met het gevoel er genoeg van te hebben en de kinderen lastig hanteerbaar vinden. Afstand daarentegen hangt hoofdzakelijk negatief samen met het delen van positieve momenten met kinderen. Ook contextuele variabelen hebben interacties met kenmerken van ouderlijke burn-out, en dat illustreert dat het relevant is om ouderschap te onderzoeken binnen de context van het gezinssysteem. Als toekomstig onderzoek de hoofdrol van uitputting bij het ontstaan van een ouderlijke burn-out bevestigt, kan preventie worden gericht op het verminderen van uitputting bij ouders.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362.

Le mogamulizumab (moga), anticorps monoclonal anti-CCR4, a montré une augmentation de la survie sans progression (SSP) dans le mycosis fongoïde (MF) et le syndrome de Sézary (SS) où il est approuvé en 2e ligne. Des rémissions de longue durée ont été décrites, mais les données sur les stratégies d’arrêt et l’évolution après arrêt manquent. Nous avons conduit une étude pour évaluer l’évolution des patients atteints de SS ayant arrêté le moga pour tout autre motif qu’une progression de la maladie.

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.govas #NCT02153580.

Éaluer l’intérêt de l’implantation cochléaire (IC) bilatérale sur le développement perceptif et linguistique des enfants sourds atteints de fœtopathie à cytomégalovirus (CMV).

Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas. CD-NSCs were given every 2 weeks using an indwelling brain catheter, followed each time by a 7-d course of oral 5-FC (and leucovorin in the final patient cohort). Fifteen evaluable patients received a median of 4 (range 2–10) intracerebral CD-NSC doses; doses were escalated from 50 × 106to 150 × 106CD-NSCs. Neuropharmacokinetic data confirmed that CD-NSCs continuously produced 5-FU in the brain during the course of 5-FC. There were no clinical signs of immunogenicity, and only three patients developed anti-NSC antibodies. Our results suggest intracerebral administration of serial doses of CD-NSCs is safe and feasible and identified a recommended dose for phase II testing of 150 × 106CD-NSCs.

IMPORTANCE: Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in the central nervous system. Such information is critical for advancing checkpoint antibody therapies for treatment of brain tumors. OBJECTIVE: To evaluate pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid (CSF) after intravenous administration. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid and blood samples were collected from 10 adult patients with high-grade gliomas who were participating in clinical trials of intracranially administered chimeric antigen receptor (CAR) T cells and intravenous pembrolizumab at City of Hope in Duarte, California, from 2017 through 2019. Neuropharmacokinetic and immunologic correlative studies were performed on CSF and serum samples. INTERVENTIONS OR EXPOSURES: Pembrolizumab, 200 mg, was given intravenously every 3 weeks with a median of 2 cycles (range, 1-8). CAR T cells were administered intracranially every 1 to 4 weeks. Cerebrospinal fluid and blood samples were collected on the day of CAR T-cell administration and then 24 hours later for a total of 100 paired samples. MAIN OUTCOMES AND MEASURES: Pembrolizumab concentrations were measured by enzyme-linked immunosorbent assay, PD-1 blocking on T cells by flow cytometry, and results of PD-1 blockade on CAR T-cell function by in vitro tumor rechallenge assays. RESULTS: Of the 10 patients included in this study, the mean (SD) age was 45.7 (11.0) years, and 6 (60%) were women. Steady-state pembrolizumab concentrations in the CSF were achieved by 24 hours after initial intravenous administration, with a mean CSF:serum ratio of 0.009 (95% CI, 0.004-0.014). The CSF concentrations of pembrolizumab effectively blocked PD-1 on both endogenous T cells and intracranially administered CAR T cells in the CSF, with flow cytometric detection of surface PD-1 on the T cells decreasing from a mean (SD) of 39.3% (20.2%) before pembrolizumab to a mean (SD) of 3.8% (5.8%) 24 hours after pembrolizumab infusion. Steady-state concentrations in the CSF were maintained throughout the 21-day cycle of pembrolizumab, as was the PD-1 blocking effect, evidenced by no increase in detectable surface PD-1 on T cells in the CSF during that time period. Incubation of PD-1–expressing T cells with CSF samples from patients treated with pembrolizumab also resulted in PD-1 blockade. CONCLUSIONS AND RELEVANCE: Results of this study demonstrate steady-state concentrations of pembrolizumab in CSF after intravenous administration as well as CSF concentrations that are sufficient for blocking PD-1 on endogenous and adoptively transferred T cells. This provides mechanistic insight regarding the ability of systemically administered PD-1 blocking antibodies to modulate T-cell activity in the brain.

L’implant cochléaire (IC) a permis à une proportion croissante de patients sourds d’entrer dans la communication orale. Bien que les bénéfices de l’implantation bilatérale soient connus, beaucoup d’enfants et d’adolescents ne sont porteurs que d’un IC. L’objectif était d’évaluer l’apport d’une IC séquentielle et l’influence de certains facteurs sur ces résultats.

Le contexte de la réimplantation cochléaire (réIC) chez l’enfant sourd implanté est parfois complexe. L’objectif de cette étude est de décrire les orientations initiales motivant la réIC, d’analyser le diagnostic final et de proposer un algorithme décisionnel.

Le 26 septembre 2019, à Rouen, un important incendie industriel a engendré un large panache de fumées noires, associé à des retombées de suies, et a été à l'origine de fortes odeurs d'hydrocarbure. Une étude épidémiologique avait pour objectif d’évaluer les conséquences de l'accident, un an après sa survenue, sur la santé mentale de la population exposée.

Un incendie industriel est survenu à Rouen (France) en 2019, provoquant un panache de fumées, des retombées de suies et des odeurs ressenties pendant plusieurs semaines. Cette étude avait pour objectif d’évaluer, un an après, la qualité de vie en lien avec la santé des personnes exposées aux conséquences de cet incendie.

La prise en compte du retentissement psychologique d’un fait de violence dans la détermination d’une durée d’incapacité totale de travail (ITT) paraît aujourd’hui indispensable. Cependant, les méthodes de détermination d’une ITT « psychologique » ne font à ce jour ni l’objet d’un consensus, ni l’objet de recommandations.

Swelling clay minerals are formed with two tetrahedral sheets (silica) sandwiching an octahedral sheet forming the 2:1 layer. Due to isomorphic substitutions by less charged cations in either the tetrahedral or octahedral sheet, the solid layer bears a net negative charge that is compensated by interlayer cations that can control the hydration properties. In this paper we study the hydration of synthetic saponite clay samples by combining inelastic neutron scattering (INS) experiments and ab initio quantum calculations, that include normal modes analysis and ab initio molecular dynamics simulations (AIMD). The first part of the paper focuses on the dry clay sample. The model used for the calculations was validated by a thorough comparison between INS results and ab initio calculations. Normal mode analysis provided a clear assignment of the different vibrational bands of dry saponite. Furthermore, as oriented samples were used in the INS experiment, it was possible to observe clear anisotropy effects thus confirming the two-dimensional (2D) nature of the system. The second part of the paper analyzes the hydration properties of both low- and high-charge saponite samples by combining INS experiments and AIMD calculations. The shift to higher energies of the librational bands of interlayer water upon increasing hydration is thus revealing a stronger H-bond network of interlayer water. The agreement between calculated vibrational density profile, AIMD, and grand canonical Monte Carlo simulations shows that a combined INS/density functional theory (DFT) study allows performing studies that avoid some of the common drawbacks linked to the use of empirical force fields.

To describe changes in palliative care characteristics, utilisation and outcomes in Victoria during a period of enhanced public health management and a prolonged lockdown due to coronavirus disease 2019.

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo–expanded autologous central memory–enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 106 in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8+ TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4+ and CD8+ TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4+/CD8+ TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.

L’objectif principal était d’évaluer, dans une large cohorte clinique multicentrique de patients avec un syndrome d’apnées obstructives du sommeil (SAOS), les prévalences et facteurs indépendamment associés au SAOS positionnelle prédominant (POSA, [IAHD/IAHND≥2]) et exclusif (e-POSA, [OSA+IAHND<5]). L’objectif secondaire était d’évaluer le résultat du traitement par pression positive continue (PPC) pour les patients souffrant de POSA et d’e-POSA.

These preclinical studies of ferumoxytol‐labeled neural stem cells (NSCs) for magnetic resonance imaging (MRI) cell tracking led to U.S. FDA approval for first‐in‐human use of this labeling method for NSCs transplanted into brain tumor patients. Ferumoxytol labeling of NSCs did not affect cell viability, growth kinetics, or tumor tropism, and enabled MRI visualization of NSC distribution in vivo. These studies support the clinical development of ferumoxytol labeling of cells for post‐transplant MRI visualization and tracking. Numerous stem cell‐based therapies are currently under clinical investigation, including the use of neural stem cells (NSCs) as delivery vehicles to target therapeutic agents to invasive brain tumors. The ability to monitor the time course, migration, and distribution of stem cells following transplantation into patients would provide critical information for optimizing treatment regimens. No effective cell‐tracking methodology has yet garnered clinical acceptance. A highly promising noninvasive method for monitoring NSCs and potentially other cell types in vivo involves preloading them with ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to enable cell tracking using magnetic resonance imaging (MRI). We report here the preclinical studies that led to U.S. Food and Drug Administration approval for first‐in‐human investigational use of ferumoxytol to label NSCs prior to transplantation into brain tumor patients, followed by surveillance serial MRI. A combination of heparin, protamine sulfate, and ferumoxytol (HPF) was used to label the NSCs. HPF labeling did not affect cell viability, growth kinetics, or tumor tropism in vitro, and it enabled MRI visualization of NSC distribution within orthotopic glioma xenografts. MRI revealed dynamic in vivo NSC distribution at multiple time points following intracerebral or intravenous injection into glioma‐bearing mice that correlated with histological analysis. Preclinical safety/toxicity studies of intracerebrally administered HPF‐labeled NSCs in mice were also performed, and they showed no significant clinical or behavioral changes, no neuronal or systemic toxicities, and no abnormal accumulation of iron in the liver or spleen. These studies support the clinical use of ferumoxytol labeling of cells for post‐transplant MRI visualization and tracking.

Epizootic bovine abortion (EBA), a tick-transmitted disease of pregnant cattle grazing foothill pastures, is a major cause of reproductive failure in California and adjacent states. Affected fetuses develop a chronic disease, resulting in late-term abortion or premature calving. Despite investigations spanning 50 years, to the authors' knowledge, the etiologic agent of EBA has not yet been isolated from affected fetuses or the tick vector. The diagnosis of EBA is based on gross and microscopic lesions. Recently, documentation that the etiologic agent is susceptible to antibiotics and identification of a unique 16S deltaproteobacterial rDNA gene sequence in 90% of thymus tissues from aborted fetuses have supported the role of a bacterial infection as the cause of EBA. To determine whether bacteria could be detected in the tissues, histochemical staining and immunohistochemical procedures were used on formalin-fixed, paraffin-embedded tissues. Use of a modified Steiner silver stain revealed small numbers of intracytoplasmic bacterial rods in 37 of 42 thymic samples from EBA-affected fetuses. Improved detection was achieved by use of immunohistochemical staining with serum from EBA-affected fetuses that resulted in detection of numerous bacterial rods in the cytoplasm of histiocytic cells in the thymus from all 42 EBA-affected fetuses. Immunohistochemical examination of additional tissues from 21 field and experimental EBA cases revealed positively stained intracytoplasmic bacterial rods in many organs with inflammatory lesions. Use of the modified Steiner stain and immunohistochemical staining of tissues from negative-control fetuses failed to reveal organisms. To the authors' knowledge, this is the first report to document morphologic evidence of a bacterium associated with the lesions of EBA.

Abstract: Classical atomistic simulation techniques have been used to investigate the energies of hydrogen defects in Mg2SiO4 and Mg2GeO4 spinels. Ringwoodite (γ-Mg2SiO4) is considered to be the most abundant mineral in the lower part of the transition zone and can incorporate large amounts of water in the form of hydroxyls, whereas the germanate spinel (γ-Mg2GeO4) corresponds to a low-pressure structural analogue for ringwoodite. The calculated defect energies indicate that the most favourable mechanisms for hydrogen incorporation are coupled either with the reduction of ferric iron or with the creation of tetrahedral vacancies. Hydrogen will go preferentially into tetrahedral vacancies, eventually leading to the formation of the hydrogarnet defect, before associating with other negatively charged point defects. The presence of isolated hydroxyls is not expected. The same trend is observed for germanate, and thus γ-Mg2GeO4 could be used as a low-pressure analogue for ringwoodite in studies of water-related defects and their effect on physical properties.

Abstract: We have developed a new interatomic potential model for the simulation of ringwoodite, the high-pressure phase of Mg2SiO4, and its low-pressure analogue, Mg2GeO4 spinel. The main novelty is the addition of a breathing shell model that enables us to accurately describe the structural and elastic parameters of both spinels up to 15 GPa. Our model has also been applied to the two other Mg2SiO4 polymorphs in order to test its transferability. We find that although it is able to reproduce the structure and physical properties of wadsleyite, the breathing shell description is less successful with forsterite. The Mott-Littleton method has been used to calculate the energy of the intrinsic point defects in both spinels. The results indicate that these phases are likely to have the same defect population with the MgO partial Schottky defect predominating.

AbstractThe kinetics of hydrogen mobility in grossular with a chemically homogeneous composition of Gr83.2 And14.3 Py2.2 were studied by sequential annealing experiments monitored by Fourier transform infrared spectroscopy. Slices of single crystals <0.5 mm thick were annealed at temperatures in the range 1073–1323 K at ambient pressure in air and in gas mixtures of Ar(90%)/D2(10%)and Ar(90%)/H2(10%). The change of total infrared (IR) absorbance in the OH-stretching region (3700–3500 cm–1) and the OD-stretching region (2750–2580 cm–1) was used to calculate the diffusion coefficients. The law for diffusion of deuterium is given by D= D0exp[–102±45 kJ mol–1/ RT] with log D0(m2/s) = –7.6. For hydrogen extraction in air the diffusion law is expressed by D= D0exp[–323±46 kJ mol–1/RT] with log D0(m2/s) = 1.0. This activation energy agrees with the values found for Dora Maira pyrope and for other pyropes from mantle xenoliths, but the diffusivity is slower for the grossular. A detailed investigation of the decrease in individual OH bands during hydrogen extraction in air revealed two different kinds of kinetics behaviour, suggesting that at least two different types of OH defects are present in this grossular.

Kinetics of hydrogen extraction were investigated by FTIR spectroscopy on a Dora Maira pyrope single crystal. Annealing experiments were performed at ambient pressure, between 1073 and 1323 K, and under two different redox conditions ( pO 2=0.21 atm and pO 2 ≈ 10 −16 atm). During hydrogen extraction the two principal OH absorption bands behave independently. The OHa triplet, centred on 3651 cm −1, decreases at least five times faster than the OHb band at 3602 cm −1. This suggests the presence of two distinct H defects, each with its own kinetics, which are slightly dependent on oxygen partial pressure: Both kinetics are slower than previous data (Wang et al. 1996), but activation energies are similar. At the same time as the OHa bands decrease, an exchange of hydrogen from OHa to OHb occurs. The extent of this transfer can be modelled by assuming it is directly proportional to the fraction of OHa band which has been removed, independent of temperature. This suggests that OHb defects could be produced by partial dehydrogenation of OHa defects. Activation energies and values of diffusion coefficients are very close to those found by Kohlstedt and Mackwell (1998) for the diffusion of metal vacancies in olivine. Thus it is very likely that cation vacancies control the kinetics of dehydrogenation reactions in pyrope.

The prevalence of symptoms suggesting distal symmetric polyneuropathy (DSP) was reported to be higher among deployed veterans (DV) to the Persian Gulf in 1990–1991 than to control non-deployed veterans (NDV). The authors therefore compared the prevalence of DSP by direct examination of DV and their spouses to control NDV and spouses.

Ferrocenes containing phenyl and pentafluorophenyl substituents on the cyclopentadienyl rings have been prepared, and their solid-state structures were determined by single-crystal X-ray studies. In the homoleptic ferrocene Fe(Me2PhCp)2 (5), no intra- or intermolecular face-to-face π-stacking of the aryl rings is observed, as expected. The intramolecular conformation has staggered cyclopentadienyl rings with the phenyl groups in an anti conformation. However, the mixed ferrocene Fe(Me2PhCp)(C6F5Cp) (6) crystallizes with eclipsed cyclopentadienyl rings and intramolecular π-stacking between the phenyl and pentafluorophenyl substituents. In addition the π-stacking between phenyl and pentafluorophenyl rings occurs between neighboring molecules, and controls the intermolecular crystal motif. Yet a different molecular architecture is observed in the homoleptic ferrocene Fe(C6F5Cp)2 (2) which crystallizes surprisingly with intramolecularly π-stacked pentafluorophenyl rings. The overall crystal architecture in this case in controlled by π-stacking between pentafluorophenyl rings on one molecule with the cyclopentadienyl rings of neighbors, to afford a third structural motif. These results illustrate that both the intra- and intermolecular solid-state structures of simple organometallic molecules can be controlled by stacking interactions involving pentafluorophenyl rings and suggest that these attractive interactions can be added to the repertoire of attractive forces used to effect crystal engineering in organometallic systems.

Background:CD19-targeted chimeric antigen receptor T cell (CD19CART) therapy has been shown to be safe and effective for patients with relapsed/ refractory (r/r) diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, there is limited data in other types of B-cell NHLs, especially those with central nervous system (CNS) involvement. Accumulating evidence suggests that using a memory T cell starting population to manufacture CD19CAR T cells improves the efficacy of therapy (Wang et al. Blood;127: 2980). Here we report the results of our Phase 1 trial evaluating CD19CART generated using naïve and stem cell memory (Tn/mem) T cells to treat adult patients with all types of r/r B-NHL (NCT02153580).

Siddiqi: Oncternal: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang: Pepromene Bio, Inc.: Consultancy. Popplewell: Novartis: Other: Travel; Pfizer: Other: Travel; Hoffman La Roche: Other: Food. Herrera: ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Merck: Consultancy, Research Funding; Takeda: Consultancy; Gilead Sciences: Research Funding; Kite, a Gilead Company: Research Funding; AstraZeneca: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy. Budde: Mustang Bio, Inc: Research Funding; Merck, Inc: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; IGM Biosciences: Research Funding; Roche: Consultancy; Gilead: Consultancy; Novartis: Consultancy; AstraZeneca: Research Funding. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Brown: Mustang Bio: Patents & Royalties, Research Funding; Chimeric therapeutics: Patents & Royalties, Research Funding. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company.CD19-directed CAR T cell therapy manufactured at City of Hope being used for relapsed/refractory B-cell NHL.