E2F1 mediates competition, proliferation and response to cisplatin in cohabitating resistant and sensitive ovarian cancer cells.

Background: Tumor heterogeneity is one of the key factors leading to chemo-resistance relapse. It remains unknown how resistant cancer cells influence sensitive cells during cohabitation and growth within a heterogenous tumors. The goal of our study was to identify driving factors that mediate the interactions between resistant and sensitive cancer cells and to determine the effects of cohabitation on both phenotypes. Methods: We used isogenic ovarian cancer (OC) cell lines pairs, sensitive and resistant to platinum: OVCAR5 vs. OVCAR5 CisR and PE01 vs. PE04, respectively, to perform long term direct culture and to study the phenotypical changes of the interaction of these cells. Results: Long term direct co-culture of sensitive and resistant OC cells promoted proliferation (p < 0.001) of sensitive cells and increased the proportion of cells in the G1 and S cell cycle phase in both PE01 and OVCAR5 cells. Direct co-culture led to a decrease in the IC50 to platinum in the cisplatin-sensitive cells (5.92 µM to 2.79 µM for PE01, and from 2.05 µM to 1.51 µM for OVCAR5). RNAseq analysis of co-cultured cells showed enrichment of Cell Cycle Control, Cyclins and Cell Cycle Regulation pathways. The transcription factor E2F1 was predicted as the main effector responsible for the transcriptomic changes in sensitive cells. Western blot and qRT-PCR confirmed upregulation of E2F1 in co-cultured vs monoculture. Furthermore, an E2F1 inhibitor reverted the increase in proliferation rate induced by co-culture to baseline levels. Conclusion: Our data suggest that long term cohabitation of chemo-sensitive and -resistant cancer cells drive sensitive cells to a higher proliferative state, more responsive to platinum. Our results reveal an unexpected effect caused by direct interactions between cancer cells with different proliferative rates and levels of platinum resistance, modelling competition between cells in heterogeneous tumors.

Control of ZIF-62 and ag ZIF-62 Film Thickness within Asymmetric Tubular Supports through Pressure and Dose Time Variation of Atomic Layer Deposition.

Thin-films of metal-organic frameworks (MOFs) have widespread potential applications, especially with the emergence of glass-forming MOFs, which remove the inherent issue of grain boundaries and allow coherent amorphous films to be produced. Herein, it is established that atomic layer deposition (ALD) of zinc oxide lends excellent control over the thickness and localization of resultant polycrystalline and glass zeolitic imidazole framework-62 (ZIF-62) thin-films within tubular α-alumina supports. Through the reduction of the chamber pressure and dose times during zinc oxide deposition, the resultant ZIF-62 films are reduced from 38 µm to 16 µm, while the presence of sporadic ZIF-62 (previously forming as far as 280 µm into the support) is prevented. Furthermore, the glass transformation shows a secondary reduction in film thickness from 16 to 2 µm.

Reduced healthcare access contributes to delay of care in endometrial cancer.

OBJECTIVE: We aimed to characterize delays to care in patients with endometrioid endometrial cancer and the role healthcare access plays in these delays. METHODS: A chart review was performed of patients with endometrioid endometrial cancer who presented with postmenopausal bleeding at a diverse, urban medical center between 2006 and 2018. The time from symptom onset to treatment was abstracted from the medical record. This interval was subdivided to assess for delay to presentation, delay to diagnosis, and delay to treatment. RESULTS: We identified 484 patients who met the inclusion criteria. The median time from symptom onset to treatment was 4 months with an interquartile range of 2 to 8 months. Most patients had stage I disease at diagnosis (88.6%). There was no significant difference in race/ethnicity or disease stage at time of diagnosis between different groups. Patients who had not seen a primary care physician or general obstetrician-gynecologist in the year before symptom onset were more likely to have significantly delayed care (27.7% vs 14.3%, p = 0.02) and extrauterine disease (20.2% vs 4.9%, p < 0.01) compared to those with established care. Black and Hispanic patients were more likely to experience significant delays from initial biopsy to diagnosis. CONCLUSIONS: Delays exist in the evaluation of endometrial cancer. This delay is most pronounced in patients without an established outpatient primary care provider or obstetrician-gynecologist.

Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers.

OBJECTIVE: To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic. METHODS: In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests. RESULTS: Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025). CONCLUSIONS: Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

Anti-Fouling Properties of Phosphonium Ionic Liquid Coatings in the Marine Environment.

Biofouling is the buildup of marine organisms on a submerged material. This research tests the efficacy of phosphonium ion gels comprising phosphonium monomers ([P444VB][AOT] and [P888VB][AOT]) and free ionic liquid ([P4448][AOT], [P88814][AOT]) (10 to 50 wt%), varying copper(II) oxide biocide concentrations (0 to 2 wt%), and the docusate anion [AOT]- for added hydrophobicity. The efficacy of these formulations was tested using a seachest simulator protected from light and tidal currents in New Zealand coastal waters over the summer and autumn periods. Anti-fouling performance was correlated with the hydrophobicity of the surface (water contact angle: 14-131°) and biocide concentration. Formulations with higher hydrophobicity (i.e., less free ionic liquid and longer alkyl chain substituents) displayed superior anti-fouling performance. The presence of the copper(II) biocide negatively affected anti-fouling performance via significant increases to hydrophilicity. No correlation was observed between antimicrobial activity and anti-fouling performance. Overall, phosphonium ion gels show potential for combining anti-fouling and foul release properties.

Effect of continuous post-operative lidocaine infusion in an enhanced recovery program on opioid use following gynecologic oncology surgery.

OBJECTIVE: To determine the effectiveness of implementing an Enhanced Recovery After Surgery (ERAS) program, including continuous intraoperative and postoperative intravenous (IV) lidocaine infusion, on perioperative opioid use. METHODS: This was a single-institution retrospective pre- post- cohort study. Consecutive patients undergoing planned laparotomy for known or potential gynecologic malignancy were identified after implementation of an ERAS program and compared to a historical cohort. Opioid use was calculated as morphine milligram equivalents (MMEs). Cohorts were compared using bivariate tests. RESULTS: A total of 215 patients were included in the final analysis, 101 patients received surgery before ERAS implementation and 114 received surgery after. A reduction in total opioid use was observed in ERAS patients compared with historical controls (MME 26.5 [9.6-60.8] versus 194.5 [123.8-266.8], p<0.001). Length of stay (LOS) was reduced by 25% in the ERAS cohort (median 3 days, range 2-26, versus 4 days, range 2-18; p<0.001). Within the ERAS cohort, 64.9% received IV lidocaine for the planned 48 hours, and 5.6% had the infusion discontinued early. Within the ERAS cohort, patients who received IV lidocaine infusion used less opioids compared to those who did not (median 16.9, range 5.6-55.1, versus 46.2, range 23.2-76.1; p<0.002). CONCLUSION: An ERAS program including a continuous IV lidocaine infusion as the opioid-sparing analgesic strategy was noted to be safe and effective, leading to decreased opioid consumption and LOS compared with a historic cohort. Additionally, lidocaine infusion was noted to decrease opioid consumption even among patients already receiving other ERAS interventions.

An Upper Bound Visualization of Design Trade-Offs in Adsorbent Materials for Gas Separations: CO2 , N2 , CH4 , H2 , O2 , Xe, Kr, and Ar Adsorbents.

The last 20 years have seen many publications investigating porous solids for gas adsorption and separation. The abundance of adsorbent materials (this work identifies 1608 materials for CO2 /N2 separation alone) provides a challenge to obtaining a comprehensive view of the field, identifying leading design strategies, and selecting materials for process modeling. In 2021, the empirical bound visualization technique was applied, analogous to the Robeson upper bound from membrane science, to alkane/alkene adsorbents. These bound visualizations reveal that adsorbent materials are limited by design trade-offs between capacity, selectivity, and heat of adsorption. The current work applies the bound visualization to adsorbents for a wider range of gas pairs, including CO2 , N2 , CH4 , H2 , Xe, O2 , and Kr. How this visual tool can identify leading materials and place new material discoveries in the context of the wider field is presented. The most promising current strategies for breaking design trade-offs are discussed, along with reproducibility of published adsorption literature, and the limitations of bound visualizations. It is hoped that this work inspires new materials that push the bounds of traditional trade-offs while also considering practical aspects critical to the use of materials on an industrial scale such as cost, stability, and sustainability.

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.

BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

Successful management of stage IV epithelioid trophoblastic tumor using multimodality treatment: A case report.

Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia (GTN) that develops from chorionic-type intermediate trophoblast, is more resistant to chemotherapy than choriocarcinoma, and presents with metastatic disease in 25-35% of cases. We report a case of a 32-year-old who presented one week postpartum with severe abdominal pain and was found to have profound anemia and an elevated hCG level. CT scans and MRI revealed bleeding from hepatic masses, multiple hemorrhagic pulmonary nodules, a 7 cm uterine mass, and brain metastases. She underwent emergent hepatic embolization, was started on induction chemotherapy with weekly low-dose etoposide and cisplatin followed by a transition to etoposide, high-dose methotrexate, actinomycin D, etoposide, and cisplatin (HD EMA-EP), received stereotactic brain radiotherapy, and subsequently underwent minimally-invasive hysterectomy. She remains disease free over one year after the completion of treatment. An aggressive multimodal treatment approach employing etoposide/cisplatin-based chemotherapy as well as surgical procedures to control hemorrhage or excise resistant disease, and radiotherapy for brain metastases can result in successful treatment of stage IV ETT.

An upper bound visualization of design trade-offs in adsorbent materials for gas separations: alkene/alkane adsorbents.

The last 20 years has seen an explosion in the number of publications investigating porous solids for gas adsorption and separation. The combination of external drivers such as anthropogenic climate change and industrial efficiency has been coupled with discovery of new materials such as synthetic zeolites, metal-organic frameworks, covalent organic frameworks, and non-porous adsorbents. Numerous reviews catalogue these materials and their properties. However, the field lacks a unifying resource to visually compare and analyse materials properties with regard to their utility as a scientific advance and potential for industrial use. In the related field of membrane science, the 'Robeson upper bound' empirically describes the trade-off between gas permeability and selectivity and has become a ubiquitous tool for comparing membrane materials. In this article, we propose upper and lower bounds that empirically correlate the trade-offs encountered when designing adsorbent materials for gas separation, specifically: capacity, selectivity, and heat of adsorption. We apply bound visualizations to adsorbents studied for light alkene/alkane separations and highlight their use in identifying candidate materials for examination within process models and for guiding insights to the most effective materials design strategies. Furthermore, we note the limitations of upper and lower bound visualizations and provide links to a database resource for researchers to produce and download bound visualization plots. We anticipate that introducing bound visualizations to the field of adsorbents for gas separations will allow researchers to provide context for the importance of new materials discoveries, understand trade-offs in adsorbent design, and connect process engineers with candidate materials.

Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes.

We have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.

Isolable 1-Butene Copper(I) Complexes and 1-Butene/Butane Separation Using Structurally Adaptable Copper Pyrazolates.

Non-porous small molecule adsorbents such as {[3,5-(CF3 )2 Pz]Cu}3 (where Pz=pyrazolate) are an emerging class of materials that display attractive features for ethene-ethane separation. This work examines the chemistry of fluorinated copper(I) pyrazolates {[3,5-(CF3 )2 Pz]Cu}3 and {[4-Br-3,5-(CF3 )2 Pz]Cu}3 with much larger 1-butene in both solution and solid state, and reports the isolation of rare 1-butene complexes of copper(I), {[3,5-(CF3 )2 Pz]Cu(H2 C=CHC2 H5 )}2 and {[4-Br-3,5-(CF3 )2 Pz]Cu(H2 C=CHC2 H5 )}2 and their structural, spectroscopic, and computational data. The copper-butene adduct formation in solution involves olefin-induced structural transformation of trinuclear copper(I) pyrazolates to dinuclear mixed-ligand systems. Remarkably, larger 1-butene is able to penetrate the dense solid material and to coordinate with copper(I) ions at high molar occupancy. A comparison to analogous ethene and propene complexes of copper(I) is also provided.

Discrepancies between author- and industry-reported disclosures of financial relationships at an annual gynecologic oncology research meeting.

OBJECTIVE: Trillions of dollars pass to physicians from industry-related businesses annually, leading to many opportunities for financial conflicts of interest. The Open Payments Database (OPD) was created to ensure transparency. We describe the industry relationships as reported in the OPD for presenters at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting and evaluate concordance between author disclosures of their financial interests and information provided by the OPD. METHODS: This is an observational, cross-sectional study. Disclosure data were collected from authors with oral and featured abstract presentations in the 2019 SGO annual conference. These disclosures were compared to data available for each author in the 2018 OPD, which included the amount and nature of industry payments. RESULTS: We examined the disclosures of 301 authors who met inclusion criteria. Of 161 authors who had disclosure statements on their presentations,147 reported "no disclosures," and 14 disclosed industry relationships. The remaining 140 did not list any disclosure information. Sixty percent (184/301) of authors had industry relationships in the 2018 OPD, including 173 of 287 (60.3%) of authors who either reported no disclosures or did not have disclosure data available in their presentations. These transactions totaled over 43 million USD from 122 different companies, with most payments (46%) categorized as "Research or Associated Research." Accurate disclosure reporting was associated with receiving higher payments or research payments, and being a presenting author. CONCLUSIONS: Most authors at the SGO annual conference did not correctly disclose their industry relationships when compared with their entries in the OPD.

Overcoming Fundamental Limitations in Adsorbent Design: Alkene Adsorption by Non-porous Copper(I) Complexes.

Purifying alkenes from alkanes requires cryogenic distillation. This consumes energy equivalent to countries of ca. 5 million people. Replacing distillation with adsorption processes would significantly increase energy efficiency. Trade-offs between kinetics, selectivity, capacity, and heat of adsorption have prevented production of an optimal adsorbent. We report adsorbents that overcome these trade-offs. [Cu-Br]3 and [Cu-H]3 are air-stable trinuclear complexes that undergo reversible solid-state inter-molecular rearrangements to produce dinuclear [Cu-Br⋅(alkene)]2 and [Cu-H⋅(alkene)]2 . The reversible solid-state rearrangement, confirmed in situ using powder X-ray diffraction, allows adsorbent design trade-offs to be overcome, coupling low heat of adsorption (-10 to -17 kJ mol-1alkene ), high alkene:alkane selectivity (47; 29), and uptake capacity (>2.5 molalkene mol-1Cu3 ). Most remarkably, [Cu-H]3 displays fast uptake and regenerates capacity within 10 minutes.

Vaporization, bioactive formulations and a marine natural product: different perspectives on antivirals.

This article examines three aspects of antivirals, such as hydroxychloroquine, chloroquine, and remdesvir, as they might relate to the treatment of a viral infection such as COVID-19: (i) the use of vaporization for the delivery of antivirals, with the bulk constituents having mild antiviral efficacy; (ii) the application of a marine natural product extract as opposed to a single molecule as an antiviral agent; and (iii) a counter intuitive approach to formulation that is, in part, based on delivering multiple species that fall into three categories: building blocks for the virus to accelerate replication; an energy source for the infected cell to boost its immune response; and the species that antagonize or provide toxicity to the virus.

Comment on Metabolomics for a Millenniums-Old Crop: Tea Plant (Camellia sinensis).

Metabolomics is the study of metabolite profiles at the system level. Since its introduction in the early 2000s, metabolomics has greatly contributed to the understanding of the distribution of metabolites in organisms under various physiological conditions. In this comment, we show our research on the temporal development of metabolomics in general and in agricultural, food, and nutritional sciences. According to our investigation, metabolomics develops in a sigmoid kinetics. On the basis of the analysis, we made a prediction on the future of the metabolomics study, which may benefit the research community in the field.

MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment.

Open Science has changed research by making data accessible and shareable, contributing to replicability to accelerate and disseminate knowledge. However, for rodent cognitive studies the availability of tools to share and disseminate data is scarce. Automated touchscreen-based tests enable systematic cognitive assessment with easily standardised outputs that can facilitate data dissemination. Here we present an integration of touchscreen cognitive testing with an open-access database public repository (mousebytes.ca), as well as a Web platform for knowledge dissemination (https://touchscreencognition.org). We complement these resources with the largest dataset of age-dependent high-level cognitive assessment of mouse models of Alzheimer's disease, expanding knowledge of affected cognitive domains from male and female mice of three strains. We envision that these new platforms will enhance sharing of protocols, data availability and transparency, allowing meta-analysis and reuse of mouse cognitive data to increase the replicability/reproducibility of datasets.