CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer

The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.United States. National Institutes of Health (R01CA148688)United States. National Institutes of Health (R01CA148688S1)United States. National Institutes of Health (R01CA179483-01)United States. National Institutes of Health (CA109901)United States. National Institutes of Health (HG002668)United States. National Institutes of Health (R21HG006778)American Cancer Society (RSG-12-247-TBG)United States. Department of Defense (PR120741A)Friends for Life Neuroblastoma Foundatio

Inpatient Opioid Use Varies by Construct Length Among Laminoplasty Versus Laminectomy and Fusion Patients

BACKGROUND: Laminoplasty (LP) and laminectomy and fusion (LF) are utilized to achieve decompression in patients with symptomatic degenerative cervical myelopathy (DCM). Comparative analyses aimed at determining outcomes and clarifying indications between these procedures represent an area of active research. Accordingly, we sought to compare inpatient opioid use between LP and LF patients and to determine if opioid use correlated with length of stay. METHODS: Sociodemographic information, surgical and hospitalization data, and medication administration records were abstracted for patients \u3e18 years of age who underwent LP or LF for DCM in the Mass General Brigham (MGB) health system between 2017 and 2019. Specifically, morphine milligram equivalents (MME) of oral and parenteral pain medication given after arrival in the recovery area until discharge from the hospital were collected. Categorical variables were analyzed using chi-squared analysis or Fisher exact test when appropriate. Continuous variables were compared using Independent samples RESULTS: One hundred eight patients underwent LF, while 138 patients underwent LP. Total inpatient opioid use was significantly higher in the LF group (312 vs. 260 MME, p=.03); this difference was primarily driven by higher postoperative day 0 pain medication requirements. Furthermore, more LF patients required high dose (\u3e80 MME/day) regimens. While length of stay was significantly different between groups, with LF patients staying approximately 1 additional day, postoperative day 0 MME was not a significant predictor of this difference. When operative levels including C2, T1, and T2 were excluded, the differences in total opioid use and average length of stay lost significance. CONCLUSIONS: Inpatient opioid use and length of stay were significantly greater in LF patients compared to LP patients; however, when constructs including C2, T1, T2 were excluded from analysis, these differences lost significance. Such findings highlight the impact of operative extent between these procedures. Future studies incorporating patient reported outcomes and evaluating long-term pain needs will provide a more complete understanding of postoperative outcomes between these 2 procedures

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Dielectrophoresis Aligned Single-Walled Carbon Nanotubes as pH Sensors

Here we report the fabrication and characterization of pH sensors using aligned single-walled carbon nanotubes (SWNTs). The SWNTs are dispersed in deionized (DI) water after chemical functionalization and filtration. They are deposited and organized on silicon substrates with the dielectrophoresis process. Electrodes with “teeth”-like patterns—fabricated with photolithography and wet etching—are used to generate concentrated electric fields and strong dielectrophoretic forces for the SWNTs to deposit and align in desired locations. The device fabrication is inexpensive, solution-based, and conducted at room temperature. The devices are used as pH sensors with the electrodes as the testing pads and the dielectrophoretically captured SWNTs as the sensing elements. When exposed to aqueous solutions with various pH values, the SWNTs change their resistance accordingly. The SWNT-based sensors demonstrate a linear relationship between the sensor resistance and the pH values in the range of 5–9. The characterization of multiple sensors proves that their pH sensitivity is highly repeatable. The real-time data acquisition shows that the sensor response time depends on the pH value, ranging from 2.26 s for the pH-5 solution to 23.82 s for the pH-9 solution. The long-term stability tests illustrate that the sensors can maintain their original sensitivity for a long period of time. The simple fabrication process, high sensitivity, and fast response of the SWNT-based sensors facilitate their applications in a wide range of areas

Carbon Fiber Implants in Orthopaedic Oncology

Carbon fiber offers numerous material benefits including reduced wear, high strength-to-weight ratio, a similar elastic modulus to that of bone, and high biocompatibility. Carbon fiber implants are increasingly used in multiple arenas within orthopaedic surgery, including spine, trauma, arthroplasty, and oncology. In the orthopaedic oncologic population, the radiolucency of carbon fiber facilitates post-operative imaging for tumor surveillance or recurrence, the monitoring of bony healing and union, and radiation mapping and delivery