We present Atacama Large Millimeter/submillimeter Array and Multi-Unit Spectroscopic Explorer observations of the brightest cluster galaxy in Abell 2597, a nearby (z = 0.0821) cool core cluster of ...galaxies. The data map the kinematics of a three billion solar mass filamentary nebula that spans the innermost 30 kpc of the galaxy's core. Its warm ionized and cold molecular components are both cospatial and comoving, consistent with the hypothesis that the optical nebula traces the warm envelopes of many cold molecular clouds that drift in the velocity field of the hot X-ray atmosphere. The clouds are not in dynamical equilibrium, and instead show evidence for inflow toward the central supermassive black hole, outflow along the jets it launches, and uplift by the buoyant hot bubbles those jets inflate. The entire scenario is therefore consistent with a galaxy-spanning "fountain," wherein cold gas clouds drain into the black hole accretion reservoir, powering jets and bubbles that uplift a cooling plume of low-entropy multiphase gas, which may stimulate additional cooling and accretion as part of a self-regulating feedback loop. All velocities are below the escape speed from the galaxy, and so these clouds should rain back toward the galaxy center from which they came, keeping the fountain long lived. The data are consistent with major predictions of chaotic cold accretion, precipitation, and stimulated feedback models, and may trace processes fundamental to galaxy evolution at effectively all mass scales.
The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as ...gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood–brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.
We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution ...single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.
Understanding the responses of tundra systems to global change has global implications. Most tundra regions lack sustained environmental monitoring and one of the only ways to document multi-decadal ...change is to resample historic research sites. The International Polar Year (IPY) provided a unique opportunity for such research through the Back to the Future (BTF) project (IPY project #512). This article synthesizes the results from 13 papers within this Ambio Special Issue. Abiotic changes include glacial recession in the Altai Mountains, Russia; increased snow depth and hardness, permafrost warming, and increased growing season length in sub-arctic Sweden; drying of ponds in Greenland; increased nutrient availability in Alaskan tundra ponds, and warming at most locations studied. Biotic changes ranged from relatively minor plant community change at two sites in Greenland to moderate change in the Yukon, and to dramatic increases in shrub and tree density on Herschel Island, and in subarctic Sweden. The population of geese tripled at one site in northeast Greenland where biomass in non-grazed plots doubled. A model parameterized using results from a BTF study forecasts substantial declines in all snowbeds and increases in shrub tundra on Niwot Ridge, Colorado over the next century. In general, results support and provide improved capacities for validating experimental manipulation, remote sensing, and modeling studies.
Gastroenterology fellowships need to ensure that trainees achieve competence in upper endoscopy (EGD) and colonoscopy. Because the impact of structured feedback remains unknown in endoscopy training, ...this study compared the effect of structured feedback with standard feedback on trainee learning curves for EGD and colonoscopy.
In this multicenter, cluster, randomized controlled trial, trainees received either individualized quarterly learning curves or feedback standard to their fellowship. Assessment was performed in all trainees using the Assessment of Competency in Endoscopy tool on 5 consecutive procedures after every 25 EGDs and colonoscopies. Individual learning curves were created using cumulative sum (CUSUM) analysis. The primary outcome was the mean CUSUM score in overall technical and overall cognitive skills.
In all, 13 programs including 132 trainees participated. The intervention arm (6 programs, 51 trainees) contributed 558 EGD and 600 colonoscopy assessments. The control arm (7 programs, 81 trainees) provided 305 EGD and 468 colonoscopy assessments. For EGD, the intervention arm (–.7 standard deviation {SD}, 1.3) had a superior mean CUSUM score in overall cognitive skills compared with the control arm (1.6 SD, .8, P = .03) but not in overall technical skills (intervention, –.26 SD, 1.4; control, 1.76 SD, .7; P = .06). For colonoscopy, no differences were found between the 2 arms in overall cognitive skills (intervention, –.7 SD, 1.3; control, .7 SD, 1.3; P = .95) or overall technical skills (intervention, .1 SD, 1.5; control, –.1 SD, 1.5; P = .77).
Quarterly feedback in the form of individualized learning curves did not affect learning curves for EGD and colonoscopy in a clinically meaningful manner. (Clinical trial registration number: NCT02891304.)
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We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and ...selectively binds to STAT5 over STAT3, inhibits STAT5–SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5′s downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.
This report updated an analysis of a 14‐year experience of moderately high‐dose (4500 to 5000 cGy) preoperative radiation as an adjuvant to low anterior resection of 95 cases of adenocarcinoma of the ...rectum. The treatment was well tolerated without treatment‐related mortality and with a low incidence (5.2%) of severe complications. The local recurrence rate was 4.2%, and distant failure rate was 10.5%. At 5 years, the actuarial survival rate was 66% and the disease‐free survival rate was 64%. At 10 years, the actuarial survival rate and disease‐free survival rate were 52%. The authors concluded that moderately high‐dose (4500 to 5000 cGy) neoadjuvant radiation in clinically resectable adenocarcinoma of the rectum in which one segment of the anastomosis was in the preoperative radiation field is a safe, effective adjuvant to low anterior resection and that it offered patients excellent local control, long‐term survival, and sphincter preservation. Results could be enhanced by chemotherapy, and the authors urged well‐designed prospective randomized multicenter trials to determine the most appropriate drugs, dosage, and sequencing of co‐adjuvant preoperative radiation therapy and chemotherapy with surgery.
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