Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal ...residual disease by flow cytometry (FCM-MRD
) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10
/kg and were eventually settled at 1 × 10
/kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD
patients achieved MRD
. All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD
with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10
/kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epithelial-mesenchymal transition (EMT) is an essential component of metastasis. Our previous study demonstrated that cancer-associated fibroblasts (CAFs) induce EMT in lung cancer cells. In recent ...years, many studies have demonstrated that CAFs induce metastasis and drug resistance in cancer cells via exosomes.
We sought to discover the mechanism underlying how CAFs induce EMT in lung cancer cells, unveiling the role of exosomes in lung cancer progression.
We cultured lung cancer cell (i) with control medium, normal fibroblasts (NFs) or CAFs; (ii) with SNAI1-transfected or NC (negative control)-transfected CAFs; (iii) with exosomes extracted from NF- or CAF-conditioned medium; (iv) with exosomes released by SNAI1 or NC-transfected CAFs; (v) with CAF-conditioned medium or exosome-depleted CAF-conditioned medium.
qRT-PCR was conducted to examine the expression of CDH1 (gene of E-cadherin) and VIM (gene of Vimentin), western blotting was conducted to examine E-cadherin and vimentin levels in lung cancer cells.
Exosomes released by CAFs-promoted EMT in lung cancer cells. Interestingly, SNAI1 levels in exosomes secreted from CAFs were correlated with SNAI1 expression in CAFs. Furthermore, the level of SNAI1 in exosomes was crucial for inducing EMT in lung cancer cells. Finally, treatment of CAFs with GW4869, an inhibitor of exosome release, noticeably inhibited their EMT-inducing effect on recipient epithelial cells.
The molecular mechanism underlying how CAFs induce EMT in cancer cells may be that CAFs deliver SNAI1 to recipient cancer cells via exosomes.
Endocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of ...epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.
ABSTRACT We compute upper limits on the nanohertz-frequency isotropic stochastic gravitational wave background (GWB) using the 9 year data set from the North American Nanohertz Observatory for ...Gravitational Waves (NANOGrav) collaboration. Well-tested Bayesian techniques are used to set upper limits on the dimensionless strain amplitude (at a frequency of 1 yr−1) for a GWB from supermassive black hole binaries of A gw < 1.5 × 10 − 15 . We also parameterize the GWB spectrum with a broken power-law model by placing priors on the strain amplitude derived from simulations of Sesana and McWilliams et al. Using Bayesian model selection we find that the data favor a broken power law to a pure power law with odds ratios of 2.2 and 22 to one for the Sesana and McWilliams prior models, respectively. Using the broken power-law analysis we construct posterior distributions on environmental factors that drive the binary to the GW-driven regime including the stellar mass density for stellar-scattering, mass accretion rate for circumbinary disk interaction, and orbital eccentricity for eccentric binaries, marking the first time that the shape of the GWB spectrum has been used to make astrophysical inferences. Returning to a power-law model, we place stringent limits on the energy density of relic GWs, gw ( f ) h 2 < 4.2 × 10 − 10 . Our limit on the cosmic string GWB, gw ( f ) h 2 < 2.2 × 10 − 10 , translates to a conservative limit on the cosmic string tension with G < 3.3 × 10 − 8 , a factor of four better than the joint Planck and high-l cosmic microwave background data from other experiments.
Coaxing vibrations in the regimes of both large mass and high temperature into their motional quantum ground states is extremely challenging, because it requires an ultra-high optical power, which ...introduces extraneous excessive heating and intricate instabilities. Here we propose how to overcome these obstacles and cool vibrational networks by simply harnessing the power of an exceptional point (EP) induced in parity-time symmetric structures; and we reveal its exceptional cooling properties otherwise unachievable in conventional devices. In stark contrast to standard-cooling protocols, a three orders-of-magnitude amplification in net cooling rates arises from the EP-cooling mechanism, without which it vanishes. Remarkably, our EP cooling is nearly immune to both resonator mass and environmental temperature, and this overthrows the consensus that poor intrinsic factors and rugged extrinsic environment suppress cooling channels. Our study offers the possibility of isolating and engineering motional properties of large-mass and high-temperature objects for various applications in optical and acoustic sensing, gravimetry, and inertial navigation.
BACKGROUND Total steroidal saponins of Paris polyphylla Sm. var. yunnanensis (TSSP) have been widely used in China for the treatment of abnormal uterine bleeding (AUB). But until now, the main active ...constituents and the mechanisms underlying the pharmacological actions on uterine activity have not been described. METHODS Total steroidal saponins were extracted with EtOH and purified by chromatography. In vitro isometric contraction studies were performed using myometrial strips from estrogen-primed or pregnant rats. Intracellular calcium was monitored under a confocal microscope using Fluo-3 AM-loaded myometrial cells. RESULTS TSSP dose-dependently induced phasic myometrial contractions in vitro. Experiments with calcium channel blockers or kinase inhibitors demonstrated that the TSSP-stimulated myometrial contraction was mediated by an increase in Ca2+i via influx of extracellular calcium and release of intracellular calcium. Through bioassay-guided separation, it was found that total spirostanol saponins exhibited contractile activity in myometrium and Pennogenin-3-O-α-L-arabinofuranosyl(1→4)α-l-rhamnopyranosyl(1→2)-β-d-glucopyranoside (PARG) was identified as the active ingredient of TSSP. Furthermore, the contractile response of rat myometrium to PARG was significantly enhanced with advancing pregnancy. CONCLUSIONS These data provide evidence that myometrial contractility stimulated by TSSP results from Ca2+i increase and supports the possibility that some spirostanol gylcosides may represent a new type of contractile agonist for the uterus.
Complex conductivity of soils Revil, A.; Coperey, A.; Shao, Z. ...
Water resources research,
August 2017, Volume:
53, Issue:
8
Journal Article
Peer reviewed
Open access
The complex conductivity of soils remains poorly known despite the growing importance of this method in hydrogeophysics. In order to fill this gap of knowledge, we investigate the complex ...conductivity of 71 soils samples (including four peat samples) and one clean sand in the frequency range 0.1 Hz to 45 kHz. The soil samples are saturated with six different NaCl brines with conductivities (0.031, 0.53, 1.15, 5.7, 14.7, and 22 S m−1, NaCl, 25°C) in order to determine their intrinsic formation factor and surface conductivity. This data set is used to test the predictions of the dynamic Stern polarization model of porous media in terms of relationship between the quadrature conductivity and the surface conductivity. We also investigate the relationship between the normalized chargeability (the difference of in‐phase conductivity between two frequencies) and the quadrature conductivity at the geometric mean frequency. This data set confirms the relationships between the surface conductivity, the quadrature conductivity, and the normalized chargeability. The normalized chargeability depends linearly on the cation exchange capacity and specific surface area while the chargeability shows no dependence on these parameters. These new data and the dynamic Stern layer polarization model are observed to be mutually consistent. Traditionally, in hydrogeophysics, surface conductivity is neglected in the analysis of resistivity data. The relationships we have developed can be used in field conditions to avoid neglecting surface conductivity in the interpretation of DC resistivity tomograms. We also investigate the effects of temperature and saturation and, here again, the dynamic Stern layer predictions and the experimental observations are mutually consistent.
Plain Language Summary
Geophysical methods are increasingly popular in agriculture. Usually, DC (DIrect Current) resistivity is the preferred method but the interpretation of resistivity data suffers a major flaw: the inability to distinguish between bulk and surface conductivity. This has yield to unrealistc interpretation schemes in hydrogeophysics and an abuse of Archie's law. We propose a way to cure this flaw by extending the DC resistivity method to what is called induced polarization. This paper is the first work entirely focused on the study of induced polarization of soils including a comparison with a mechanistic model and a study of the influence of both temperature and saturation.
Key Points
A large data set of complex conductivity data on soils is presented
Complex conductivity data are explained to the light of the dynamic Stern layer model
Surface conductivity is related to the normalized chargeability or quadrature conductivity, which opens new perspectives in hydrogeophysics
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Pneumoperitoneum and nonphysiological positioning required for robotic surgery increase cardiopulmonary risk because of the use of larger airway pressures (Paws) to maintain tidal volume (VT). ...However, the quantitative partitioning of respiratory mechanics and transpulmonary pressure (PL) during robotic surgery is not well described. We tested the following hypothesis: (1) the components of driving pressure (transpulmonary and chest wall components) increase in a parallel fashion at robotic surgical stages (Trendelenburg and robot docking); and (2) deep, when compared to routine (moderate), neuromuscular blockade modifies those changes in PLs as well as in regional respiratory mechanics.
We studied 35 American Society of Anesthesiologists (ASA) I-II patients undergoing elective robotic surgery. Airway and esophageal balloon pressures and respiratory flows were measured to calculate respiratory mechanics. Regional lung aeration and ventilation was assessed with electrical impedance tomography and level of neuromuscular blockade with acceleromyography. During robotic surgical stages, 2 crossover randomized groups (conditions) of neuromuscular relaxation were studied: Moderate (1 twitch in the train-of-four stimulation) and Deep (1-2 twitches in the posttetanic count).
Pneumoperitoneum was associated with increases in driving pressure, tidal changes in PL, and esophageal pressure (Pes). Steep Trendelenburg position during robot docking was associated with further worsening of the respiratory mechanics. The fraction of driving pressures that partitioned to the lungs decreased from baseline (63% ± 15%) to Trendelenburg position (49% ± 14%, P < .001), due to a larger increase in chest wall elastance (Ecw; 12.7 ± 7.6 cm H2O·L) than in lung elastance (EL; 4.3 ± 5.0 cm H2O·L, P < .001). Consequently, from baseline to Trendelenburg, the component of Paw affecting the chest wall increased by 6.6 ± 3.1 cm H2O, while PLs increased by only 3.4 ± 3.1 cm H2O (P < .001). PL and driving pressures were larger at surgery end than at baseline and were accompanied by dorsal aeration loss. Deep neuromuscular blockade did not change respiratory mechanics, regional aeration and ventilation, and hemodynamics.
In robotic surgery with pneumoperitoneum, changes in ventilatory driving pressures during Trendelenburg and robot docking are distributed less to the lungs than to the chest wall as compared to routine mechanical ventilation for supine patients. This effect of robotic surgery derives from substantially larger increases in Ecw than ELs and reduces the risk of excessive PLs. Deep neuromuscular blockade does not meaningfully change global or regional lung mechanics.
BACKGROUND:Pneumoperitoneum and nonphysiological positioning required for robotic surgery increase cardiopulmonary risk because of the use of larger airway pressures (Paws) to maintain tidal volume ...(VT). However, the quantitative partitioning of respiratory mechanics and transpulmonary pressure (PL) during robotic surgery is not well described. We tested the following hypothesis(1) the components of driving pressure (transpulmonary and chest wall components) increase in a parallel fashion at robotic surgical stages (Trendelenburg and robot docking); and (2) deep, when compared to routine (moderate), neuromuscular blockade modifies those changes in PLs as well as in regional respiratory mechanics.
METHODS:We studied 35 American Society of Anesthesiologists (ASA) I-II patients undergoing elective robotic surgery. Airway and esophageal balloon pressures and respiratory flows were measured to calculate respiratory mechanics. Regional lung aeration and ventilation was assessed with electrical impedance tomography and level of neuromuscular blockade with acceleromyography. During robotic surgical stages, 2 crossover randomized groups (conditions) of neuromuscular relaxation were studiedModerate (1 twitch in the train-of-four stimulation) and Deep (1–2 twitches in the posttetanic count).
RESULTS:Pneumoperitoneum was associated with increases in driving pressure, tidal changes in PL, and esophageal pressure (Pes). Steep Trendelenburg position during robot docking was associated with further worsening of the respiratory mechanics. The fraction of driving pressures that partitioned to the lungs decreased from baseline (63% ± 15%) to Trendelenburg position (49% ± 14%, P < .001), due to a larger increase in chest wall elastance (Ecw; 12.7 ± 7.6 cm H2O·L) than in lung elastance (EL; 4.3 ± 5.0 cm H2O·L, P < .001). Consequently, from baseline to Trendelenburg, the component of Paw affecting the chest wall increased by 6.6 ± 3.1 cm H2O, while PLs increased by only 3.4 ± 3.1 cm H2O (P < .001). PL and driving pressures were larger at surgery end than at baseline and were accompanied by dorsal aeration loss. Deep neuromuscular blockade did not change respiratory mechanics, regional aeration and ventilation, and hemodynamics.
CONCLUSIONS:In robotic surgery with pneumoperitoneum, changes in ventilatory driving pressures during Trendelenburg and robot docking are distributed less to the lungs than to the chest wall as compared to routine mechanical ventilation for supine patients. This effect of robotic surgery derives from substantially larger increases in Ecw than ELs and reduces the risk of excessive PLs. Deep neuromuscular blockade does not meaningfully change global or regional lung mechanics.
Aims/hypothesis
The generation of induced pluripotent stem cells (iPSCs) provides a promising possibility for type 1 diabetes therapy. However, the generation of insulin-producing cells from iPSCs ...and evaluation of their efficacy and safety should be achieved in large animals before clinically applying iPSC-derived cells in humans. Here we try to generate insulin-producing cells from rhesus monkey (RM) iPSCs.
Methods
Based on the knowledge of embryonic pancreatic development, we developed a four-stage protocol to generate insulin-producing cells from RM iPSCs. We established a quantitative method using flow cytometry to analyse the differentiation efficiency. In addition, to evaluate the differentiation competence and function of RM iPSC-derived cells, transplantation of stage 3 and 4 cells into immunodeficient mice was performed.
Results
RM iPSCs were sequentially induced to definitive endoderm (DE), pancreatic progenitors (PP), endocrine precursors (EP) and insulin-producing cells. PDX1
+
PP cells were obtained efficiently from RM iPSCs (over 85% efficiency). The TGF-β inhibitor SB431542 promoted the generation of NGN3
+
EP cells, which can generate insulin-producing cells in vivo upon transplantation. Finally, after this four-stage differentiation in vitro, insulin-producing cells that could secrete insulin in response to glucose stimulation were obtained. When transplanted into mouse models for diabetes, these insulin-producing cells could decrease blood glucose levels in approximately 50% of the mice.
Conclusions/interpretation
We demonstrate for the first time that RM iPSCs can be differentiated into functional insulin-producing cells, which will provide the basis for investigating the efficacy and safety of autologous iPSC-derived insulin-producing cells in a rhesus monkey model for type 1 diabetes therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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