Nuclear morphology is shaped by loop-extrusion programs.

It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces1-3. However, how polymorphonuclear structures are assembled remains unknown4. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin5-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.

Breast Cancer Patients' Preferred Source and Timing of Nutrition Information.

It is important that breast cancer patients know where they can access evidence-based nutrition information because misinformation may lead to confusion for patients regarding dietary requirements, as well as potentially causing harm to health. There are gaps in knowledge about where and when patients seek nutrition information. Our exploratory study used telephone interviews to investigate where patients with breast cancer obtained nutrition information pre and postdiagnosis, and their preferred sources and timing for receiving nutrition information. We interviewed 29 women diagnosed with breast cancer who had attended the Cross Cancer Institute in Edmonton, Alberta. The structured interview included 13 closed-ended questions and 1 open-ended question. Interviews revealed that motives for seeking nutrition information changed between pre and postdiagnosis, but the sources did not. The majority of participants did not access a registered dietitian (RD) postdiagnosis but did specify that meeting with a RD would be their preferred source of information. Responses varied for the preferred sources and timing of nutrition information provision. Our study suggests that further research is necessary to know how to best meet the nutrition information needs of patients diagnosed with breast cancer.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

Standardized Discharge Planning Tool Leads to Earlier Discharges and Fewer Readmissions.

BACKGROUND: In an inpatient setting, aspects of discharge planning are often left to the provider's memory, leading to errors, inefficiencies, and avoidable costs. METHODS: A multidisciplinary team of oncology practitioners used process improvement methodologies to redesign the discharge planning process. INTERVENTIONS: The primary intervention was an evidence-based discharge planning tool, called the discharge navigator, used from admission through discharge. RESULTS: Thirty-day unplanned readmission rates decreased by 29.0% from preimplementation (March 2017 through August 2017) to postimplementation (September 2017 through March 2020). The percentage of patients discharged before noon increased 76.2%. A comparable service not utilizing the intervention saw lesser or no improvement in these measures. CONCLUSION: The tool provided a systematic approach to discharge planning. Key design elements included a centralized location within the electronic health record and an electronic shortcut to populate the tool. Although developed for a specialized population, most elements are applicable to any hospitalized patient.

StomaphyX vs a sham procedure for revisional surgery to reduce regained weight in Roux-en-Y gastric bypass patients : a randomized clinical trial.

IMPORTANCE: Revisional laparoscopic surgery after Roux-en-Y gastric bypass (RYGB) has been linked to substantial complications and morbidity. OBJECTIVE: To investigate the safety and effectiveness of endoscopic gastric plication with the StomaphyX device vs a sham procedure for revisional surgery in RYGB patients to reduce regained weight. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center, randomized, single-blinded study from July 2009 through February 2011, evaluating revisional surgery using StomaphyX was conducted in patients with initial weight loss after RYGB performed at least 2 years earlier. We planned for 120 patients to be randomized 2:1 to multiple full-thickness plications within the gastric pouch and stoma using the StomaphyX device with SerosFuse fasteners or a sham endoscopic procedure and followed up for 1 year. The primary efficacy end point was reduction in pre-RYGB excess weight by 15% or more excess body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) loss and BMI less than 35 at 12 months after the procedure. Adverse events were recorded. RESULTS: Enrollment was closed prematurely because preliminary results indicated failure to achieve the primary efficacy end point in at least 50% of StomaphyX-treated patients. One-year follow-up was completed by 45 patients treated with StomaphyX and 29 patients in the sham treatment group. Primary efficacy outcome was achieved by 22.2% (10) with StomaphyX vs 3.4% (1) with the sham procedure (P < .01). Patients undergoing StomaphyX treatment experienced significantly greater reduction in weight and BMI at 3, 6, and 12 months (P ≤ .05). There was one causally related adverse event with StomaphyX, that required laparoscopic exploration and repair. CONCLUSIONS AND RELEVANCE: StomaphyX treatment failed to achieve the primary efficacy target and resulted in early termination of the study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00939055.