The rockefeller university

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL)(1). Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)(2-4), the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)(2,5). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden(2-4). CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity(2-9). Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.

Objective: Sleep can affect quality of life (QoL) during cancer survivorship, and symptoms related to poor sleep can be exacerbated. We examined the prevalence, severity, and nature of subjective sleep complaints in women surviving stage I-III breast cancer who were 1-10 years posttreatment. We also examined the demographic, medical, physical, and psychosocial correlates of poor sleep in these women in order to identify the subgroups that may be most in need of intervention. Method: A total of 200 patients at a comprehensive cancer center who were 1-10 years posttreatment for primary stage I-III breast cancer with no evidence of disease at the time of enrollment completed a battery of questionnaires on demographics, sleep, physical symptoms, mood, cancer-specific fears, and QoL. Results: The women had a mean age of 57 years (SD = 10.0), with a mean of 63.3 months (SD = 28.8) of post-cancer treatment. Some 38% of these patients were identified as having poor-quality sleep. Women with poor sleep took longer to fall asleep, had more awakenings, and acquired 2 hours less sleep per night than those with good sleep. They also had a lower QoL, greater severity of pain, more concerns about health and recurrence, and increased vasomotor symptoms (p < 0.05). Daytime sleepiness and depression were found to be not significantly correlated with sleep quality. Significance of results: Many breast cancer survivors had severe subjective insomnia, and several breast cancer survivor subgroups were identified as having members who might be most in need of sleep-improvement interventions. Addressing physical symptoms (e.g., vasomotor symptoms and pain) and providing education about the behavioral, social, environmental, and medical factors that affect sleep could result in substantial improvement in the life course of breast cancer survivors.

A search for dark matter is conducted in events with large missing transverse momentum and a hadronically decaying, Lorentz-boosted top quark. This study is performed using proton-proton collisions at a center-of-mass energy of 13 TeV, in data recorded by the CMS detector in 2016 at the LHC, corresponding to an integrated luminosity of 36 fb(-1). New substructure techniques, including the novel use of energy correlation functions, are utilized to identify the decay products of the top quark. With no significant deviations observed from predictions of the standard model, limits are placed on the production of new heavy bosons coupling to dark matter particles. For a scenario with purely vector-like or purely axial-vector-like flavor changing neutral currents, mediator masses between 0.20 and 1.75 TeV are excluded at 95% confidence level, given a sufficiently small dark matter mass. Scalar resonances decaying into a top quark and a dark matter fermion are excluded for masses below 3.4 TeV, assuming a dark matter mass of 100 GeV.

The nuclear modification factors of J/psi and psi(2S) mesons are measured in PbPb collisions at a centre-of-mass energy per nucleon pair of root S-NN = 5.02 TeV. The analysis is based on PbPb and pp data samples collected by CMS at the LHC in 2015, corresponding to integrated luminosities of 464 mu b(-1) and 28 pb(-1), respectively. The measurements are performed in the dimuon rapidity range of vertical bar y vertical bar < 2.4 as a function of centrality, rapidity, and transverse momentum (p(T)) from p(T) = 3 GeV/c in the most forward region and up to 50 GeV/c. Both prompt and nonprompt (coming from b hadron decays) J/psi mesons are observed to be increasingly suppressed with centrality, with a magnitude similar to the one observed at root S-NN = 2.76 TeV for the two J/psi meson components. No dependence on rapidity is observed for either prompt or nonprompt J/psi mesons. An indication of a lower prompt J/psi meson suppression at p(T) > 25 GeV/c is seen with respect to that observed at intermediate p(T). The prompt psi(2S) meson yield is found to be more suppressed than that of the prompt J/psi mesons in the entire p(T) range.

The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche.

Recent studies have identified a specialized subset of CD31(hi)endomucin(hi) (CD31(hi)EMCN(hi)) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31(hi)EMCN(hi) endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31(hi)EMCN(hi) endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31(hi)EMCN(hi) endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3(-/-) mice. This coupling between osteo-blasts and CD31(hi)EMCN(hi) endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.

A search is presented for single production of heavy vector-like quarks (B) that decay to a Higgs boson and a b quark, with the Higgs boson decaying to a highly boosted b (b) over bar pair reconstructed as a single collimated jet. The analysis is based on data collected by the CMS experiment in proton-proton collisions at root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The data are consistent with background expectations, and upper limits at 95% confidence level on the product of the B quark cross section and the branching fraction are obtained in the range 1.28-0.07 pb, for a narrow B quark with a mass between 700 and 1800 GeV. The production of B quarks with widths of 10, 20 and 30% of the resonance mass is also considered, and the sensitivities obtained are similar to those achieved in the narrow width case. This is the first search at the CERN LHC for the single production of a B quark through its fully hadronic decay channel, and the first study considering finite resonance widths of the B quark.

A search is presented for the associated production of a Higgs boson with a top quark pair in the all-jet final state. Events containing seven or more jets are selected from a sample of proton-proton collisions at root s = 13 TeV collected with the CMS detector at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb(-1). To separate the t (t) over barH signal from the irreducible t (t) over bar + b (b) over bar background, the analysis assigns leading order matrix element signal and background probability densities to each event. A likelihood-ratio statistic based on these probability densities is used to extract the signal. The results are provided in terms of an observed t (t) over barH signal strength relative to the standard model production cross section mu = sigma/sigma(SM), assuming a Higgs boson mass of 125 GeV. The best fit value is (mu) over cap = 0.9 +/- 0.7(stat) +/- 1.3(syst) = 0.9 +/- 1.5 (tot), and the observed and expected upper limits are, respectively, mu < 3.8 and < 3.1 at 95% confidence levels.

The sensory organs of the inner ear are challenging to study in mammals due to their inaccessibility to experimental manipulation and optical observation. Moreover, although existing culture techniques allow biochemical perturbations, these methods do not provide a means to study the effects of mechanical force and tissue stiffness during development of the inner ear sensory organs. Here we describe a method for three-dimensional organotypic culture of the intact murine utricle and cochlea that overcomes these limitations. The technique for adjustment of a three-dimensional matrix stiffness described here permits manipulation of the elastic force opposing tissue growth. This method can therefore be used to study the role of mechanical forces during inner ear development. Additionally, the cultures permit virus-mediated gene delivery, which can be used for gain- and loss-of-function experiments. This culture method preserves innate hair cells and supporting cells and serves as a potentially superior alternative to the traditional two-dimensional culture of vestibular and auditory sensory organs.

A search for a massive resonance decaying into a pair of standard model Higgs bosons, in a final state consisting of two b quark-antiquark pairs, is performed. A data sample of proton-proton collisions at a centre-of-mass energy of 13 TeV is used, collected by the CMS experiment at the CERN LHC in 2016, and corresponding to an integrated luminosity of 35.9 fb(-1). The Higgs bosons are highly Lorentz-boosted and are each reconstructed as a single large-area jet. The signal is characterized by a peak in the dijet invariant mass distribution, above a background from the standard model multijet production. The observations are consistent with the background expectations, and are interpreted as upper limits on the products of the s-channel production cross sections and branching fractions of narrow bulk gravitons and radions in warped extra-dimensional models. The limits range from 126 to 1.4 fb at 95% confidence level for resonances with masses between 750 and 3000 GeV, and are the most stringent to date, over the explored mass range. (C) 2018 The Author(s). Published by Elsevier B.V.