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Judith J Stephenson,1 Jonathon Colby Gable,2 Rebekah Zincavage,1 Gregory L Price,2 Collin Churchill,2 Emily Zhu,2 Keri Stenger,2 Mukul Singhal,1 Bal Nepal,1 Michael Grabner,1 Michael J Fisch,3 David Debono,4 Amy R Geschwender,5 Gebra Cuyun Carter2 1HealthCore, Inc., Wilmington, DE, USA; 2Eli Lilly and Company, Indianapolis, IN, USA; 3AIM Specialty Health, Chicago, IL, USA; 4Anthem, Inc., Indianapolis, IN, USA; 5SWOG Cancer Research Network, San Antonio, TX, USACorrespondence: Judith J Stephenson Tel +1 302-547-5770Email JStephenson@healthcore.comPurpose: To describe patients’ perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4& 6i’s) to treat metastatic breast cancer (MBC).Methods: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4& 6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed.Results: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues.Conclusion: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.Keywords: oral oncolytics, patient perspective, semi-structured interviews, adherence, persistence, CDK4& 6i users

Gebra Cuyún Carter,1 Maitreyee Mohanty,2 Keri Stenger,1 Claudia Morato Guimaraes,1 Shivaprasad Singuru,3 Pradeep Basa,3 Sheena Singh,3 Vanita Tongbram,2 Sherko Kuemmel,4,5 Valentina Guarneri,6 Sara M Tolaney7 1Eli Lilly and Company, Indianapolis, IN, USA; 2Global Health Economics and Outcomes Research, ICON Plc, New York, NY, USA; 3Global Health Economics and Outcomes Research, ICON Plc, Bangalore, Karnataka, India; 4Interdisciplinary Breast Unit, Kliniken Essen-Mitte (KEM), Essen, Germany; 5Charité – Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany; 6Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, PD, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, PD, Italy; 7Dana-Farber Cancer Institute, Brookline, MA, 02215, USACorrespondence: Maitreyee MohantyGlobal Health Economics and Outcomes Research, ICON Plc., New York, NY, USAEmail Maitreyee.Mohanty@iconplc.comPurpose: Advanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2– advanced breast cancer.Methods: A systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).Results: Seventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥ 50% of the population were HR+/HER2–. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.Conclusion: Multiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2– advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.Keywords: advanced breast cancer, prognostic factors, survival

The gorgonian, Leptogorgia virgulata is a temperate, colonial cnidarian, found in the sub-tidal coastal waters of the mid-Atlantic and southeastern United States. A characteristic feature of this and other gorgonians is an abundance of calcium carbonate spicules throughout the entire colony. When organisms such as this gorgonian form these calcified structures, an acidic environment is generated which then must be adjusted or the calcium carbonate will dissociate. Numerous mechanisms are involved in the removal of acidic conditions from the calcifying environment. For example, the enzyme carbonic anhydrase has been reported to function in this manner in a several calcifying organisms. Another enzyme that may also be involved in this process is urease. We propose that urease provides two functions in L. Virgulata: 1) It provides a carbon source for the production of CaC[O.sub.3]; and 2) It provides ammonia which spontaneously combines with the free [H.sup.+]ion left from the calcification process to form ammonium ions which passively diffuses out of the organism into the water. This reverses acidosis, increasing the pH, and allowing calcification to occur. In this study, immunoreactive urease protein was detected in gorgonian extracts by western blotting. Immunoreactivity appears strongest in the samples collected during the summer and fall, and weakest in samples collected in the winter. This annual pattern appears to reflect that of spicule calcification and corresponding collagenous spicule organic matrix formation. That is, organic matrix and spicule formation is greatest in the summer, drops in the winter, and initiates again in the spring. These parallel findings suggest that urease is involved in the calcification process.

It is estimated that approximately 10 to 15 million Americans have intracranial aneurysms. Intracranial aneurysms are classified as either unruptured or ruptured. Advances in knowledge and technology are enhancing diagnosis, management, and outcomes associated with unruptured intracranial aneurysms. Optimal outcomes are achieved when aneurysms are treated before they rupture. If the aneurysm ruptures, the mortality rate ranges from 30% to 60%. A review of evidence regarding aneurysms, including the pathogenesis, risk factors, treatment options, and outcomes, is presented. Treatment options addressed include surgical clipping, endovascular coiling, or watchful waiting. Current evidence supports aggressive treatment for patients with previously ruptured aneurysms, large or symptomatic aneurysms, a family history of aneurysm rupture, a long life expectancy, and aneurysms demonstrating growth. Factors that favor watchful waiting include aneurysms that are small or located in the anterior circulation and in patients with a short life expectancy or comorbid medical conditions. Nurses are in an ideal position to use evidence and outcomes to provide accurate and current information on how to reduce the risks for rupture and evaluate treatment options. [ABSTRACT FROM AUTHOR]

Dexamethasone (20 mg) or its equivalent in combination with 5-HT[SUB3] antagonists appears to be the gold-standard dose for antiemetic prophylaxis. Additional to concerns about the use of corticosteroids with respect to enhanced tumour growth or impaired killing of the tumour cells, there is evidence that high-dosage dexamethasone impairs the control of delayed nausea and emesis, whereas lower doses appear more beneficial. To come closer to the most adequate dose, we started a prospective, single-blind, randomized trial investigating additional dosage of 8 or 20 mg dexamethasone to tropisetron (Navoban), a receptor antagonist, in cis-platinum-containing (5-HT)[SUB]3 chemotherapy. After an interim analysis of 121 courses of chemotherapy in 69 patients, we have been unable to detect major differences between both treatment alternatives. High-dose dexamethasone (20 mg) had no advantage over medium-dose dexamethasone with respect to objective and subjective parameters of acute and delayed nausea and vomiting. In relation to concerns about the use of corticosteroids in non-haematological cancer chemotherapy, we suggest that 8 (mg or its equivalent should be used in combination with 5-HT)[SUB3] (antagonists until) further research proves otherwise. [ABSTRACT FROM AUTHOR]

Access to electronic medical record (EMR) patient portals made it easier for patients to quickly acquire the results of their radiology studies. However, there is little research on how well oncology patients understand the findings of radiology reports presented in the online portal without patient-physician discussion. This study assessed oncology patients' confidence and accuracy in interpreting radiology reports either with or without layman translations. A survey based on a radiology report was administered to oncology patients and caregivers. Two versions of the radiological report were randomly distributed, either a standard report or one with layman translations to evaluate participant understanding and accuracy of interpreting radiological results. Among 85 participants, a majority (67.8%) reported wanting patient portal access to radiological reports, yet less than a quarter (21.2%) felt confident in reading and interpreting radiological reports. Univariate binary logistic regression models showed that participants who read the lay report were 8 times more likely to find the radiology report easy to read. This research demonstrated that the inclusion of layman translation of standard radiology reports improves oncology patients' and caregivers' understanding of such reports with statistically significant and clinically meaningful increases in readability., (© 2022. The Author(s) under exclusive licence to American Association for Cancer Education.)

Although rodents have represented the most intensely studied animals in neurobiological investigations for more than a century, few studies have systematically compared neural and endocrine differences between wild rodents in their natural habitats and laboratory strains raised in traditional laboratory environments. In the current study, male and female Rattus norvegicus rats were trapped in an urban setting and compared to weight-and sex-matched conspecifics living in standard laboratory housing conditions. Brains were extracted for neural assessments and fecal boli were collected for endocrine [corticosterone and dehydroepiandrosterone (DHEA)] assays. Additionally, given their role in immune and stress functions, spleen and adrenal weights were recorded. A separate set of wild rats was trapped at a dairy farm and held in captivity for one month prior to assessments; in these animals, brains were processed but no hormone data were available. The results indicated that wild-trapped rats exhibited 31% heavier brains, including higher densities of cerebellar neurons and glial cells in the bed nucleus of the stria terminalis. The wild rats also had approximately 300% greater spleen and adrenal weights, and more than a six-fold increase in corticosterone levels than observed in laboratory rats. Further research on neurobiological variables in wild vs. lab animals will inform the extensive neurobiological knowledge base derived from laboratory investigations using selectively bred rodents in laboratory environments, knowledge that will enhance the translational value of preclinical laboratory rodent studies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Infrastructure professionals (N = 261) were randomly assigned to either a future or present-framed project description and asked to recommend design attributes for an infrastructure project. The future-framed condition led professionals to propose a significantly longer infrastructure design life, useful life to the community, and acceptable return on financial investment. The findings suggest a straightforward and inexpensive way to lessen present bias in various design contexts., (© 2022 The Authors.)

Microplastics pollution in marine environments is concerning. Microplastics persist and accumulate in various sections of the ocean where they present opportunity for micropollutant accumulation and microbial colonisation. Even though biofilm formation on plastics was first reported in the 1970's, it is only in recent years were plastic associated biofilms have gained research attention. Plastic surfaces pose a problem as they are a niche ready for colonisation by diverse biofilm assemblages, composed of specific bacterial communities and putative pathogens prone to acquiring ARGs and resistance in the biofilm. However, the nature of antibiotic resistance on aquatic plastic debris is not yet fully understood and remains a concern. Given the inevitable increase of plastic production and waste generation, microplastics released into the environment may prove to be problematic. This review explores microplastic waste in the ocean and possible concerns that may arise from the presence of microplastics in conjunction with favourable conditions for the development and dispersal of antibiotic resistance in the ocean and food web., (Copyright © 2021. Published by Elsevier Ltd.)

Cognitive control processes, such as updating task-relevant information while switching between multiple tasks, are substantially impaired in older adults. However, it has also been shown that these cognitive control processes can be improved by training interventions, e.g., by training in task switching. Here, we applied an event-related potential (ERP) approach to identify whether a cognitive training improves task-preparatory processes such as updating of relevant task goals. To do so, we applied a pretest-training-posttest design with eight training sessions. Two groups of older adults were either trained in task switching (treatment group) or in performing single tasks (control group) and we compared their performance to a group of untrained younger adults. To foster cue updating in the treatment group, we applied a cue-based switching task in which the two task cues were randomly selected prior to target presentation so that participants had time to prepare for the upcoming task. In contrast, the control group also received task cues but those were redundant as only one task had to be performed. We also examined whether training in cue updating during task switching can be transferred to a similar cognitive control task measuring updating of context information, namely a modified version of the AX-Continuous Performance Task (AX-CPT). The results revealed training-specific improvements in task switching, that is, a larger improvement in blocks requiring switching in comparison to single tasks at the behavioral level. In addition, training specific-effects were also found at the neuronal level. Older adults trained in cue updating while switching showed a reduction in mixing costs in the cue-related P3, indicating an improvement in preparatory updating processes. Additionally, P3 topography changed with training from a very broad to a parietally focused scalp distribution similar to the one found in younger adults. However, we did not obtain training-specific improvements in context updating in the AX-CPT neither at the behavioral level nor at the neuronal level. Results are discussed in the context of the ongoing debate on whether transfer of cognitive training improvements is possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Kray, Ferdinand and Stenger.)

The Nuclear Factor-kappa B (NF-κB) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-κB signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF-κB, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro-inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF-κB into the nucleus. NF-κB translocation occurs after its inhibitory protein, IκB-α is phosphorylated which signals for its degradation releasing NF-κB so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule-depolymerizer, NT-07-16 reduces the phosphorylation of IκB-α and also decreases the association of NF-κB with tubulin which may affect the ability of NF-κB to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-κB signaling pathway leading to less NF-κB entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages., (Copyright © 2017 Elsevier B.V. All rights reserved.)

RAW 264.7 murine macrophages were exposed to the pyrrole-based compound 3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (JG-03-14), which is a known microtubule depolymerizing agent with antitumor activity [1,2,3]. In this study exposure to JG-03-14 reduced the production of pro-inflammatory molecules by macrophages activated with lipopolysaccharide (LPS). Treatment with the pyrrole-based compound decreased the concentration of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) released from the macrophages. Exposure to JG-03-14 also decreased TNF-α mRNA expression levels and the protein expression levels of inducible nitric oxide synthase (iNOS), the enzyme responsible for NO production in the activated macrophages. Furthermore, JG-03-14 treatment significantly changed the degradation profile of IκB-β, an inhibitor of the NF-κB transcription factor, which suggests that JG-03-14 may attenuate the activation of the LPS-induced NF-κB signaling pathway needed to produce the pro-inflammatory mediators. We conclude that JG-03-14 possesses anti-inflammatory properties., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Although single nucleotide polymorphisms of the human vesicular monoamine transporter 1 (hVMAT1) gene SLC18A1 have been associated with neuropsychiatric disorders, there is limited information on the function of naturally occurring hVMAT1 variant proteins. This study evaluated transport activity of full length hVMAT1 isoform-a (NP_003044.1) with a threonine (Thr) or isoleucine (Ile) at amino acid 136 and hVMAT1 isoform-b (NP_00135796.1) with a 136-Thr and deletion of 32 amino acids in the central region of the protein. Genetic studies have previously linked the 136-Thr to bipolar disorder., Methods: Expression vectors with hVMAT1 DNA coding for isoform variants were transfected into COS-1 cells. Expression of immunoreactive proteins was assessed by Western blotting, and function was assayed by ATP-dependent transport of radiolabeled serotonin and concentration-dependent inhibition by reserpine., Results: Immunoreactive isoform-a proteins were observed as a major doublet (68-71 Kd) and a minor 39 Kd protein. The major isoform-b protein was 47 Kd with minor 57 and 115 Kd proteins. Isoform-b had no detectable transport activity, despite a large amount of immunoreactive protein. Transport activity of isoform-a with 136-Thr was 20-50% lower than with 136-Ile in time course studies (2.5-5 min) and in additional 5 min assays repeated with 5-6 transfections per variant. Kinetic analyses indicated a lower transport Vmax of isoform-a with 136-Thr but no significant differences in the transport Km or reserpine IC50., Conclusions: Deletion of amino acids 307-338 in hVMAT1 isoform-b abolishes transport activity, and a 136-Thr partially reduces activity of isoform-a.

Objective: Vesicular monoamine transporter 1 (VMAT-1) mRNA and protein were examined (1) to determine whether adult mouse brain expresses full-length VMAT-1 mRNA that can be translated to functional transporter protein and (2) to compare immunoreactive VMAT-1 proteins in brain and adrenal., Methods: VMAT-1 mRNA was detected in mouse brain with RT-PCR. The cDNA was sequenced, cloned into an expression vector, transfected into COS-1 cells, and cell protein was assayed for VMAT-1 activity. Immunoreactive proteins were examined on western blots probed with four different antibodies to VMAT-1., Results: Sequencing confirmed identity of the entire coding sequences of VMAT-1 cDNA from mouse medulla oblongata/pons and adrenal to a Gen-Bank reference sequence. Transfection of the brain cDNA into COS-1 cells resulted in transporter activity that was blocked by the VMAT inhibitor reserpine and a proton ionophore, but not by tetrabenazine, which has a high affinity for VMAT-2. Antibodies to either the C- or N- terminus of VMAT-1 detected two proteins (73 and 55 kD) in transfected COS-1 cells. The C-terminal antibodies detected both proteins in extracts of mouse medulla/pons, cortex, hypothalamus, and cerebellum but only the 73 kD protein and higher molecular weight immunoreactive proteins in mouse adrenal and rat PC12 cells, which are positive controls for rodent VMAT-1., Conclusions: These findings demonstrate that a functional VMAT-1 mRNA coding sequence is expressed in mouse brain and suggest processing of VMAT-1 protein differs in mouse adrenal and brain.

Thromboelastometry ROTEM (Pentapharm, Munich, Germany) is a viscoelastic method of whole blood clotting assessment with applications in perioperative hemostasis and hematology. The different tests available for the investigation of distinct coagulation aspects are performed with combinations of liquid reagents. The use of liquid reagents for the ROTEM measurement requires several pipetting steps, which complicates their application in clinical routine even though pipetting is performed semiautomatically. New single portion reagents (SPR) containing in one vial all lyophilized reagents necessary for each test have been recently developed. SPR require only addition of blood into the single-use reagent vial in a unique pipetting step in order to mix reagents with the blood sample. Our study compared SPR and standard liquid reagents (Pentapharm) in 21 blood samples from normal subjects and 46 samples from patients in three study centers. Following ROTEM tests were performed: EXTEM (extrinsically activated TEM), INTEM (intrinsically activated TEM), FIBTEM (fibrin-based TEM), APTEM (aprotinin-controlled TEM) and HEPTEM (heparin-insensitive TEM). In the second part of the study, the stability of SPR at 37 degrees C was also assessed on 23 blood samples in one center. Very good correlation was found between SPR and liquid reagents for all clotting parameters (correlation coefficient between 0.85-0.99). The SPR reagents showed excellent stability against thermic stress and the measurements were easier to perform than with the conventional liquid reagents system.

Objectives: Uncontrolled release of cytokines has been linked to graft dysfunction or rejection and contributes to an increase in mortality and morbidity. We argue that temporary vascular clamping of the hepatic pedicle during major hepatic surgery is a potential stimulus for an excessive release of cytokines and the activity of neutrophils., Materials and Methods: Thirty patients underwent partial liver resection or transplant. Samples were drawn preoperatively, immediately before portal vein clamping, at the early reperfusion period, and on days 1, 3, 5, and 7 after the operation. Central venous plasma concentrations of IL-6, IL-8, and TNF- a were compared to portal venous plasma. The influence of neutrophils on metabolic activity was measured by flow cytometry., Results: In both patient groups, no significant differences in cytokine concentrations between central and portal venous plasma were found. However, significant differences of neutrophils activity were observed in patients undergoing partial liver resection compared to patients after transplant., Conclusion: Portal vein stasis induced by clamping the hepatic pedicle has no influence on the local release of IL-6, IL-8, and TNF-a. However, preoperatively increased plasma levels of TNF-a play a decisive role in the metabolic activity of neutrophils in patients with final-stage liver disease.