AP-1 Mediates Cellular Adaptation and Memory Formation During Therapy Resistance.

Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective.

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, , these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment.

AdVance™ male sling for stress urinary incontinence: Long-term follow-up and patient satisfaction.

Objectives: To evaluate long-term effects, complications and satisfaction among patients treated with AdVance™ and AdVance™ XP slings (AS) at a Norwegian specialist care hospital.

Materials And Methods: Patients who had an AS implanted due to stress urinary incontinence (SUI) 2009-2016 were identified retrospectively. Demographic and perioperative data were extracted from electronic patient files.

Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies.

Augmenting Mental Health Support for Patients Accessing Different Degrees of Formal Psychiatric Care through a Supportive Text Messaging Program: Protocol for a Randomized Controlled Trial.

Patients feel more vulnerable when accessing community mental health programs for the first time or after being discharged from psychiatric inpatient units. Long wait times for follow-up appointments, shortage of mental health professionals, lack of service integration, and scarcity of tailored support can weaken their connection to the health care system. As a result, patients can present low adherence, dissatisfaction with treatment, and recurrent hospitalizations.

Allelic correlation is a marker of trade-offs between barriers to transmission of expression variability and signal responsiveness in genetic networks.

Genetic networks should respond to signals but prevent the transmission of spontaneous fluctuations. Limited data from mammalian cells suggest that noise transmission is uncommon, but systematic claims about noise transmission have been limited by the inability to directly measure it. Here, we build a mathematical framework modeling allelic correlation and noise transmission, showing that allelic correlation and noise transmission correspond across model parameters and network architectures.

Soft-Tissue Balancing in Total Hip Arthroplasty.

»: Appropriate total hip arthroplasty (THA) reconstruction must simultaneously address component position, restoration of biomechanics, and soft-tissue balance.

»: Preoperative planning for complex THA cases should include radiographic templating, a detailed case plan that contains backup implant options, and a thorough understanding of the patient's preoperative examination.

»: Using a systematic approach to soft-tissue balancing in THA enhances the ability to intraoperatively execute the preoperative plan.

Connecting veterans with smoking cessation services in less than 3 minutes.

Veterans smoke disproportionately higher (nearly 1.3 times greater) than the general population and puts them at greater risk for tobacco-related illnesses. Annual screenings by the primary care providers are conducted at Veterans Health Administration (VHA) primary care clinics, but this practice may be inadequate to overcome the chronicity of smoking.

A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering.

Mitochondrial dysfunction is associated with a spectrum of human conditions, ranging from rare, inborn errors of metabolism to the aging process. To identify pathways that modify mitochondrial dysfunction, we performed genome-wide CRISPR screens in the presence of small-molecule mitochondrial inhibitors. We report a compendium of chemical-genetic interactions involving 191 distinct genetic modifiers, including 38 that are synthetic sick/lethal and 63 that are suppressors.

The risk factors and an evidence-based protocol for the management of persistent wound drainage after total hip and knee arthroplasty.

Background: Persistent wound drainage (PWD) is one of the major risk factors for periprosthetic joint infections (PJIs), arguably the most dreaded complication after total joint arthroplasty (TJA). The aim of this study was to identify the risk factors for PWD and provide a stepwise management protocol for it.

Methods: A retrospective review of 4873 TJAs was performed.

Nordic Seas polynyas and their role in preconditioning marine productivity during the Last Glacial Maximum.

Arctic and Antarctic polynyas are crucial sites for deep-water formation, which helps sustain global ocean circulation. During glacial times, the occurrence of polynyas proximal to expansive ice sheets in both hemispheres has been proposed to explain limited ocean ventilation and a habitat requirement for marine and higher-trophic terrestrial fauna. Nonetheless, their existence remains equivocal, not least due to the hitherto paucity of sufficiently characteristic proxy data.

Effect of linseed supplementation of the gestation and lactation diets of dairy ewes on the growth performance and the intramuscular fatty acid composition of their lambs.

In this study, we investigated the effects of maternal gestation and/or lactation diets supplemented with extruded linseed (rich in 18:3n-3) on growth performance and long-chain polyunsaturated faaty acid (PUFA) accumulation in muscle tissues of suckling lambs. A total of 36 dairy ewes were fed a control diet (CON) and a diet containing linseed (LIN) during the last 8 weeks of gestation and/or the first 4 weeks of lactation. The four dietary treatments consisted of the following gestation/lactation feeding treatments: CON/CON, CON/LIN, LIN/LIN or LIN/CON.

A novel approach for determining three-dimensional acetabular orientation: results from two hundred subjects.

Background: The inherently complex three-dimensional morphology of both the pelvis and acetabulum create difficulties in accurately determining acetabular orientation. Our objectives were to develop a reliable and accurate methodology for determining three-dimensional acetabular orientation and to utilize it to describe relevant characteristics of a large population of subjects without apparent hip pathology.

Methods: High-resolution computed tomography studies of 200 patients previously receiving pelvic scans for indications not related to orthopaedic conditions were selected from our institution's database.

Implementation of paperless credentialing in a multi-state managed care organization.

Objectives: To evaluate the impact of paperless provider credentialing in a multi-state managed care organization.

Study Design: Implementation took place from June to October of 2009. A total of 6220 providers were credentialed during this study period and selected for analysis.

Documentation of fatty acid profiles in lamb meat and lamb-based infant foods.

Unlabelled: Lamb meat, when used in the weaning diet of children, is presumed to have a lower allergenicity than other forms of red meat. In children with atopic dermatitis and multiple food hypersensitivities, consumption of lamb meat has also resulted in significant clinical improvements in the severity of the eczematous lesions. Lamb meat is also of special interest in infant nutrition because it provides a somewhat unique fatty acid (FA) profile that mirrors what is thought to be optimal for neonatal growth and development.

Monitoring the volume and lateral spread of disposed sediments by acoustic methods, Oslo Harbor, Norway.

Acoustic equipment, including interferometric sonar and parametric sub-bottom profiler, have been used to determine the volume and lateral spread of dredged sediments disposed in the natural submarine depression in the Bekkelag Basin, inner Oslofjord since the beginning of the Oslo Harbor remediation project in 2006. This natural depression is used as a subaqueous confined disposal facility (CDF). Calculation of the volume of disposed sediments in the CDF is based on elevation change, derived from two high-resolution bathymetric datasets obtained in 2004, i.

CaM-kinaseII-dependent commitment to microcystin-induced apoptosis is coupled to cell budding, but not to shrinkage or chromatin hypercondensation.

The protein phosphatase inhibitor microcystin-LR (MC) induced hepatocyte apoptosis mediated by the calcium-calmodulin-dependent multifunctional protein kinase II (CaMKII). CaMKII antagonists were added at various times after MC to define for how long the cells depended on CaMKII activity to be committed to execute the various parameters of death. Shrinkage and nonpolarized budding were reversible and not coupled to commitment.

Exposure and airway effects of seafood industry workers in northern Norway.

Objective: In this study, we explored airway symptoms and exposure to bioaerosols and exhaust gases in seafood industry plants.

Methods: The study details the results from personal and environmental exposure measurements (17 plants), a questionnaire (n = 984), and clinical examinations (n = 225).

Results: The workers were exposed to allergens, endotoxins, molds, and exhaust.

Ca2+/calmodulin-dependent protein kinase II is required for microcystin-induced apoptosis.

The potent natural toxins microcystin, nodularin, and okadaic acid act rapidly to induce apoptotic cell death. Here we show that the apoptosis correlates with protein phosphorylation events and can be blocked by protein kinase inhibitors directed against the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). The inhibitors used comprised a battery of cell-permeable protein kinase antagonists and CaMKII-directed peptide inhibitors introduced by microinjection or enforced expression.

Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors.

The protein phosphatase (PP) inhibitors nodularin and microcystin-LR induced apoptosis with unprecedented rapidity, more than 50% of primary hepatocytes showing extensive surface budding and shrinkage of cytoplasm and nucleoplasm within 2 min. The apoptosis was retarded by the general caspase inhibitor Z-VAD.fmk.

Human beta-defensin-1 mRNA is transcribed in tympanic membrane and adjacent auditory canal epithelium.

The external auditory canal is less susceptible to infections than the sensitive middle-ear cavity. Since recent research has provided insight to the production of potent antimicrobial peptides from various surface epithelia, we wanted to investigate whether protection of the external auditory canal in part could be explained by the production of human beta-defensin-1 (HBD-1). This particular peptide is known to be constitutively expressed in various surface epithelia, such as airway, skin, and urogenital tissues.

8-Chloro-cAMP induces apoptotic cell death in a human mammary carcinoma cell (MCF-7) line.

8-Cl-cAMP and 8-NH2-cAMP induced MCF-7 cell death. The type(s) of cell death were studied in more detail and compared with the cell death type (apoptosis) induced by okadaic acid, an inhibitor of serine/threonine phosphatases. By morphological criteria dying cells showed loss of cell-cell interactions and microvilli, condensation of nuclear chromatin and segregation of cytoplasmic organelles.

Cyclic adenosine monophosphate (cAMP) analogs 8-Cl- and 8-NH2-cAMP induce cell death independently of cAMP kinase-mediated inhibition of the G1/S transition in mammary carcinoma cells (MCF-7).

Human mammary carcinoma cells (MCF-7) were arrested in late G1-phase after treatment with agents (forskolin, interleukin-1 beta 3-isobutyl-1-methylxanthine) that increased the endogenous concentrations of cAMP. The effect of elevated cAMP was mimicked by microinjected catalytic (C alpha) cAMP-dependent protein kinase (cAK) subunit and reversed by the injection of a dominant negative cAK regulatory mutant (RID199). Further evidence that activation of cAK induced growth arrest was provided by the use of pairs of stable cAMP analogs known to synergistically activate isolated cAK isozymes.

The choice of resuspension medium for isolated rat liver nuclei: effects on nuclear morphology and in vitro transcription.

Standard protocols for in vitro transcription assay (nuclear run-off) include 10-40% (v/v) glycerol (of various ionic strength) in the medium used for resuspension/storage of the isolated nuclei. In the present work the morphological and functional properties of nuclei isolated from rat liver have been studied as a function of the content of glycerol, sucrose and inorganic ions (K+ and Mg2+) in the resuspension medium. In contrast to earlier reports, glycerol was found not to be essential to maintain morphological integrity and RNA polymerase activity in frozen/stored nuclei.

Elevated cAMP gives short-term inhibition and long-term stimulation of hepatocyte DNA replication: roles of the cAMP-dependent protein kinase subunits.

The study reports the role of the isozyme forms (cA-PKI and cA-PKII) and subunits (R and C) of cAMP-dependent protein kinase in mediating the acute depression of hepatocyte DNA replication by elevated cAMP. Combinations of cAMP analogs preferentially activating cA-PKI or II showed that either isozyme could inhibit DNA replication. The effects of glucagon and cAMP analogs were counteracted by the cAMP antagonist RpcAMPS, implicating the necessity for cA-PK dissociation in cAMP action.