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A major paradigm shift in the diagnosis, management, and survival outcomes of early and advanced non-small cell lung cancer has transpired over the past few decades in thoracic oncology with the incorporation of molecular testing, targeted therapy, immunotherapy, neoadjuvant, and adjuvant approaches. However, transformation in the management and survival outcomes of rare lung tumors is lacking. Given the scarcity of these tumor types, randomized trials are rarely performed, and treatment is extrapolated from case series, tumor-agnostic trials, or cancers with similar histology. Literature informing the management of rare pulmonary tumors is typically limited to a single histology, unique features, or extraordinary responses to therapy. Few resources detailing genomic characteristics and delineating features of these tumors are available, often resulting in suboptimal treatment. Here, we explore the clinical, histopathologic, genomic features and potential therapies of five rare pulmonary tumors, namely adenosquamous, basaloid squamous, mucoepidermoid, carcinosarcoma, and NUT carcinoma, to build a resource for rare histological subtypes of the lung and emphasize knowledge gaps in the management of these tumors. Our recommendations are based on a comprehensive review of case reports and series, clinical trials, and the "Indiana University Experience.", Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Misty D. Shields: Received payment for speakers bureau from Jazz Pharmaceuticals, participation in advisory board for AstraZeneca and Jazz Pharmaceuticals. These relationships have ended. Katherine G. Minton: No disclosures. Peter R. Gunderman: No disclosures. Lisbeth G. Larsson: No disclosures. Shunhua Guo: No disclosures. Christopher M. Kniese: Received payment for consulting services from Cook Medical. Cynthia X. Wei: No disclosures. Julian A. Marin-Acevedo: No disclosures. Rohan Maniar: Intellectual property contributor for patent including, “TCF1 as a blood biomarker of immunotherapy response.” Greg A. Durm: Received manuscript support from Bristol Myers Squibb (payment to institution), received institutional support with grant funding for research (payment to institution) from AstraZeneca, Merck, and Mirati. Received payments for consulting services from Cook Biotech, and received payments for honoraria/presentations with Curio Sciences, DAVA Oncology, and AstraZeneca. Participated in advisory board for Curio Sciences, DAVA Oncology, and AstraZeneca. Weston He: No disclosures. Mya Tran: No disclosures. Nasser H. Hanna: Institution received grant funding for research (payment to institution) from AstraZeneca, Merck, Genentech, and Natera., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Amplification of the MYCN oncogene is found in ~20% of neuroblastoma (NB) cases and correlates with high-risk disease and poor prognosis. Despite the plethora of studies describing the role of MYCN in NB, the exact molecular mechanisms underlying MYCN's contribution to high-risk disease are not completely understood. Herein, we implemented an integrative approach combining publicly available RNA-Seq and MYCN ChIP-Seq datasets derived from human NB cell lines to define biological processes directly regulated by MYCN in NB. Our approach revealed that MYCN- amplified NB cell lines, when compared to non- MYCN -amplified cell lines, are characterized by reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. More specifically, we found genes encoding members of the γ-secretase complex, which is known for its ability to liberate several intracellular signaling molecules from membrane-bound proteins such as NOTCH receptors, to be down-regulated in MYCN- amplified NB cell lines. Analysis of MYCN ChIP-Seq data revealed an enrichment of MYCN binding at the transcription start sites of genes encoding γ-secretase complex subunits. Notably, using publicly available gene expression data from NB primary tumors, we revealed that the expression of γ-secretase subunits encoding genes and other components of the NOTCH signaling pathway was also reduced in MYCN- amplified tumors and correlated with worse overall survival in NB patients. Genetic or pharmacological depletion of MYCN in NB cell lines induced the expression of γ-secretase genes and NOTCH-target genes. Chemical inhibition of γ-secretase activity dampened the expression of NOTCH-target genes upon MYCN depletion in NB cells. In conclusion, this study defines a set of MYCN-regulated pathways that are specific to MYCN -amplified NB tumors, and it suggests a novel role for MYCN in the suppression of genes of the γ-secretase complex, with an impact on the NOTCH-target gene expression in MYCN- amplified NB.

Aim: The aim was to illuminate how nurses experience person-centred care planning using video conferencing upon hospital discharge of frail older persons., Design: Care planning via video conferencing requires collaboration, communication and information transfer between involved parties, both with regard to preparing and conducting meetings. Participation of involved parties is required to achieve a collaborative effort, but the responsibilities and roles of the involved professions are unclear, despite the existence of regulations., Method: A qualitative content analysis was conducted based on 11 individual semi-structured interviews with nurses from hospitals, municipalities and primary care in Sweden., Results: This study provides valuable insights into challenges associated with care planning via video conferencing. The meeting format, that is video conferencing, is perceived as a barrier that makes the interaction challenging. Shortcomings in video technology make a person-centred approach difficult. The person-centred approach is also difficult for nurses to maintain when the older person or relatives are not involved in the planning., (© 2022 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

The hypoxia-inducible factors (HIFs) regulate the main transcriptional pathway of response to hypoxia in T cells and are negatively regulated by von Hippel-Lindau factor (VHL). But the role of HIFs in the regulation of CD4 T cell responses during infection with M. tuberculosis isn't well understood. Here we show that mice lacking VHL in T cells (Vhl cKO) are highly susceptible to infection with M. tuberculosis, which is associated with a low accumulation of mycobacteria-specific T cells in the lungs that display reduced proliferation, altered differentiation and enhanced expression of inhibitory receptors. In contrast, HIF-1 deficiency in T cells is redundant for M. tuberculosis control. Vhl cKO mice also show reduced responses to vaccination. Further, VHL promotes proper MYC-activation, cell-growth responses, DNA synthesis, proliferation and survival of CD4 T cells after TCR activation. The VHL-deficient T cell responses are rescued by the loss of HIF-1α, indicating that the increased susceptibility to M. tuberculosis infection and the impaired responses of Vhl-deficient T cells are HIF-1-dependent., (© 2022. The Author(s).)

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions., 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 © 2022 Grinkevich, Vema, Fawkner, Issaeva, Andreotti, Dickinson, Hedström, Spinnler, Inga, Larsson, Karlén, Wilhelm, Barran, Okorokov, Selivanova and Zawacka-Pankau.)

Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells become G 1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregulates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer., Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby hampering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells., Competing Interests: A. Castell reports a patent to 2118752.1 pending. K. Fawkner reports a patent to 2118752.1 pending. L.-G. Larsson reports a patent to 2118752.1 pending. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo . Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options., Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo , suggesting its clinical applicability., Competing Interests: D. Massó-Vallés reports grants from Departament d'Empresa i Coneixement de la Generalitat de Catalunya, Spanish Ministry of Science and Innovation, European Research Council, and FERO Foundation during the conduct of the study; other from Peptomyc S.L. outside the submitted work. M. Beaulieu is a cofounder and shareholder of Peptomyc, a company focused on developing Myc inhibitors for cancer treatment. M.F. Zacarias Fluck reports other from Peptomyc S.L. outside the submitted work. L. Foradada reports personal fees from Peptomyc S.L. during the conduct of the study; personal fees from Peptomyc S.L. outside the submitted work. S. Martínez-Martín reports personal fees from Peptomyc S.L. during the conduct of the study; personal fees from Peptomyc S.L. outside the submitted work. S. Casacuberta-Serra reports personal fees from Peptomyc S.L. during the conduct of the study; personal fees from Peptomyc S.L. outside the submitted work; in addition, S. Casacuberta-Serra has a patent to EP19382194 pending. V. Castillo Cano reports other from Peptomyc S.L outside the submitted work. S. López-Estévez reports personal fees from Peptomyc SL during the conduct of the study; personal fees from Peptomyc S.L. outside the submitted work. M. Morcillo reports other from Peptomyc during the conduct of the study. J. Arribas reports grants from Roche, grants from Synthon/Byondis, grants from Molecular Partners, and grants and personal fees from Menarini during the conduct of the study; in addition, J. Arribas has a patent to P200801652 with royalties paid and a patent to EP20382457.8 with royalties paid. J.R. Whitfield reports Shareholder in Peptomyc. L. Soucek reports personal fees from Peptomyc S.L.; grants from FERO Foundation (FERO/1284), European Research Council (ERC-PoC II / 3079 / SYST-iMYC [813132]), Spanish Ministry of Science and Innovation (FI20/00274), Spanish Ministry of Science and Innovation RTC2019-007067-1), Spanish Ministry of Science and Innovation (RTC-2016-5079-1), and grants from Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya (FI-DGR-2013) during the conduct of the study; personal fees from Peptomyc S.L. outside the submitted work; in addition, L. Soucek has a patent to EP13382167.8 issued. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background The MYC oncogene is one of the most frequently altered driver genes in cancer. MYC is thus a potential target for cancer treatment as well as a biomarker for the disease. However, as a target for treatment, MYC has traditionally been regarded as "undruggable" or difficult to target. We set out to evaluate the efficacy of a novel MYC inhibitor known as MYCMI-6, which acts by preventing MYC from interacting with its cognate partner MAX. Methods MYCMI-6 response was assessed in a panel of breast cancer cell lines using MTT assays and flow cytometry. MYC gene amplification, mRNA and protein expression was analysed using the TCGA and METABRIC databases. Results MYCMI-6 inhibited cell growth in breast cancer cell lines with IC 50 values varying form 0.3 μM to >10 μM. Consistent with its ability to decrease cell growth, MYCMI-6 was found to induce apoptosis in two cell lines in which growth was inhibited but not in two cell lines that were resistant to growth inhibition. Across all breast cancers, MYC was found to be amplified in 15.3% of cases in the TCGA database and 26% in the METABRIC database. Following classification of the breast cancers by their molecular subtypes, MYC was most frequently amplified and exhibited highest expression at both mRNA and protein level in the basal subtype. Conclusions Based on these findings, we conclude that for patients with breast cancer, anti-MYC therapy is likely to be most efficacious in patients with the basal subtype.

Cellular senescence plays a role in several physiological processes including aging, embryonic development, tissue remodeling, and wound healing and is considered one of the main barriers against tumor development. Studies of normal and tumor cells both in culture and in vivo suggest that MYC plays an important role in regulating senescence, thereby contributing to tumor development. We have previously described different common methods to measure senescence in cell cultures and in tissues. Unfortunately, there is no unique marker that unambiguously defines a senescent state, and it is therefore necessary to combine measurements of several different markers in order to assure the correct identification of senescent cells. Here we describe protocols for simultaneous detection of multiple senescence markers in situ, a quantitative fluorogenic method to measure senescence-associated β-galactosidase activity (SA-β-gal), and a new method to detect senescent cells based on the Sudan Black B (SBB) analogue GL13, which is applicable to formalin-fixed paraffin-embedded tissues. The application of these methods in various systems will hopefully shed further light on the role of MYC in regulation of senescence, and how that impacts normal physiological processes as well as diseases and in particular cancer development.

Deregulated expression of the MYC oncogene is a frequent event during tumorigenesis and generally correlates with aggressive disease and poor prognosis. While MYC is a potent inducer of apoptosis, it often suppresses cellular senescence, which together with apoptosis is an important barrier against tumor development. For this latter function, MYC is dependent on cyclin-dependent kinase 2 (CDK2). Here, we utilized a MYC/BCL-X L -driven mouse model of acute myeloblastic leukemia (AML) to investigate whether pharmacological inhibition of CDK2 can inhibit MYC-driven tumorigenesis through induction of senescence. Purified mouse hematopoietic stem cells transduced with MYC and BCL-X L were transplanted into lethally irradiated mice, leading to the development of massive leukemia and subsequent death 15-17 days after transplantation. Upon disease onset, mice were treated with the selective CDK2 inhibitor CVT2584 or vehicle either by daily intraperitoneal injections or continuous delivery via mini-pumps. CVT2584 treatment delayed disease onset and moderately but significantly improved survival of mice. Flow cytometry revealed a significant decrease in tumor load in the spleen, liver and bone marrow of CVT2584-treated compared to vehicle-treated mice. This was correlated with induced senescence evidenced by reduced cell proliferation, increased senescence-associated β-galactosidase activity and heterochromatin foci, expression of p19 ARF and p21 CIP1 , and reduced phosphorylation (activation) of pRb, while very few apoptotic cells were observed. In addition, phosphorylation of MYC at Ser-62 was decreased. In summary, inhibition of CDK2 delayed MYC/BCL-X L -driven AML linked to senescence induction. Our results suggest that CDK2 is a promising target for pro-senescence cancer therapy, in particular for MYC-driven tumors, including leukemia.

Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): 'PTEN low' BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while 'PTEN high' BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy., Competing Interests: AB, AS, HJ, MF, JV, MG, OF, EF, CS, JL, JR, LL, OS No competing interests declared, (© 2020, Brunner et al.)

Introduction: The purpose of this study was to investigate inter-organisational collaboration on care planning for patients with complex care needs. Internationally, and in Sweden where the data for this study was collected, difficulties in care planning and transition of patients between the main health care providers, hospitals, municipal care, and primary care are well known., Method: A survey of a total population of care managers in hospitals, municipalities, and primary care in Sweden was conducted. The study assessed accessibility, willingness, trustworthiness, and collaboration between health care providers. Data were analysed with descriptive statistics, bivariate, and multivariate regressions., Results: The results indicate that Swedish health care providers show strong self-awareness, but they describe each other's ability to collaborate as weak. Primary care stands out, displaying the highest discrepancy between self-awareness and displayed accessibility, willingness, trustworthiness, and collaboration., Conclusion: Inability to collaborate in patient care planning may be due to shortcomings in terms of trust between caregivers in the health care organisation at a national level. Organisations that experience difficulties in collaboration tend to defend themselves with arguments about their own excellence and insufficiency of others., (© 2018 John Wiley & Sons, Ltd.)

Background: The prevalence of perioperative surgical complications is a worldwide issue: In many cases, these events are preventable. Audio-video recording during laparoscopic surgery provides useful information for the purposes of education and event analyses, and may have an impact on the focus of the surgeons operating. The aim of the present study was to investigate how audio-video recording in the operating room during laparoscopic surgery affects the focus of the surgeon and his/her assistant., Methods: A group of laparoscopic procedures where video recording only was performed was compared to a group where both audio and video recordings were made. All laparoscopic procedures were performed at Lindesberg Hospital, Sweden, during the period August to September 2017. The primary outcome was conversation not relevant to the ongoing procedure. Secondary outcomes were intra- and postoperative adverse events or complications, operation time and number of times the assistant was corrected by the surgeon., Results: The study included 41 procedures, 20 in the video only group and 21 in the audio-video group. The material comprised laparoscopic cholecystectomies, totally extraperitoneal inguinal hernia repairs and bariatric surgical procedures. Irrelevant conversation time fell from 4.2% of surgical time to 1.4% when both audio and video recordings were made (p = 0.002). No differences in perioperative adverse event or complication rates were seen., Conclusion: Audio-video recording during laparoscopic abdominal surgery reduces irrelevant conversation time and may improve intraoperative safety and surgical outcome., Trial Registration: Available at FOU Sweden (ID: 232771) and retrospectively at Clinical trials.gov (ID: NCT03425175 ; date of registration 7/2 2018).

Aims: Frail elderly patients who have multiple illnesses do not fare well in modern health care systems, mainly due to a lack of care planning and flawed communication between health professionals in different care organisations. This is especially noticeable when patients are discharged from hospital. The aim of this study was to explore health care professionals' experience of obstacles and opportunities for collaboration., Methods: Health professionals were invited to participate in three focus groups, each consisting of a hospital physician, a primary care physician, a hospital nurse, a primary care nurse, a municipal home care nurse or an assistant officer, a physical or occupational therapist and a patient or a family member representative. These individual people were then asked to discuss the obstacles and opportunities for communication between themselves and with the patients and their relatives when presented with the case report of a fictitious patient. Content analysis was used to identify categories., Results: Several obstacles were identified for effective communication and care planning: insufficient communication with patients and relatives; delayed collaboration between care-givers; the lack of an adequate responsible person for care planning; and resources not being distributed according to the actual needs of patients. The absence of an overarching responsibility for the patient, beyond organisational borders, was a recurring theme. These obstacles could also be seen as opportunities., Conclusions: Obstacles for collaboration were found on three levels: societal, organisational and individual. As health care professionals are well aware of the problems and also see solutions, management for health care should support employees' own initiatives for changes that are of benefit in the care of frail elderly patients with multiple illnesses.

MYC is a key player in tumor development, but unfortunately no specific MYC-targeting drugs are clinically available. MYC is strictly dependent on heterodimerization with MAX for transcription activation. Aiming at targeting this interaction, we identified MYCMI-6 in a cell-based protein interaction screen for small inhibitory molecules. MYCMI-6 exhibits strong selective inhibition of MYC:MAX interaction in cells and in vitro at single-digit micromolar concentrations, as validated by split Gaussia luciferase, in situ proximity ligation, microscale thermophoresis and surface plasmon resonance (SPR) assays. Further, MYCMI-6 blocks MYC-driven transcription and binds selectively to the MYC bHLHZip domain with a K D of 1.6 ± 0.5 μM as demonstrated by SPR. MYCMI-6 inhibits tumor cell growth in a MYC-dependent manner with IC 50 concentrations as low as 0.5 μM, while sparing normal cells. The response to MYCMI-6 correlates with MYC expression based on data from 60 human tumor cell lines and is abrogated by MYC depletion. Further, it inhibits MYC:MAX interaction, reduces proliferation and induces massive apoptosis in tumor tissue from a MYC-driven xenograft tumor model without severe side effects. Since MYCMI-6 does not affect MYC expression, it is a unique molecular tool to specifically target MYC:MAX pharmacologically and it has good potential for drug development.

The MYC and RAS oncogenes are sufficient for transformation of normal rodent cells. This cooperativity is at least in part based on suppression of RAS-induced cellular senescence by MYC and block of MYC-induced apoptosis by RAS - thereby canceling out two main barriers against tumor development. However, it remains unclear whether MYC and RAS cooperate in this way in human cells, where MYC and RAS are not sufficient for transformation. To address this question, we established a combined Tet-inducible H-RAS V12 and hydroxytamoxifen-inducible MycER system in normal human BJ fibroblasts. We show here that activation of RAS alone induced senescence while activation of MYC alone or together with RAS triggered DNA damage, induction of p53 and massive apoptosis, suggesting that RAS cannot rescue MYC-induced apoptosis in this system. Although coexpression with MYC reduced certain RAS-induced senescence markers (histone H3 lysine 9 trimethylation and senescence-associated β-GAL activity), the induction of the senescence marker p16INK4A was further enhanced and the culture ceased to proliferate within a few days, revealing that MYC could not fully suppress RAS-induced senescence. Furthermore, depletion of p53, which enhanced proliferation and rescued the cells from RAS-induced senescence, did not abrogate MYC-induced apoptosis. We conclude that MYC and RAS are unable to cooperate in overcoming senescence and apoptosis in normal human fibroblasts even after depletion of p53, indicating that additional oncogenic events are required to abrogate these fail-safe mechanisms and pave the way for cellular transformation. These findings have implications for our understanding of the transformation process in human cells. Abbreviations and acronyms: CDK: Cyclin-dependent kinase; DDR: DNA damage response; DOX: Doxycycline; EdU: 5-ethynyl-2'-deoxyuridine; FACS: Fluorescence Activated Cell Sorting; MycER: MYC-estrogen receptor; OHT: 4-hydroxytamoxifen; OIS: Oncogene-induced senescence; PP2A: Protein phosphatase 2A; ROS: Reactive oxygen species; SA-β-GAL: Senescence-associated β-galactosidase; SAHF: Senescence-associated heterochromatin foci; shRNA: Short hairpin RNA; YFP: Yellow fluorescent protein.

MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27 KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2), which control each other by forming a triangular network. MYC is engaged in bidirectional crosstalk with each of these players; while MYC regulates their expression and/or activity, these factors in turn modulate MYC through protein interactions and post-translational modifications including phosphorylation and ubiquitylation, impacting on MYC's transcriptional output on genes involved in cell cycle progression and senescence. Here we elaborate on these network interactions with MYC and their impact on transcription, cell cycle, replication and stress signaling, and on the role of other players interconnected to this network, such as CDK1, the retinoblastoma protein (pRB), protein phosphatase 2A (PP2A), the F-box proteins FBXW7 and FBXO28, the RAS oncoprotein and the ubiquitin/proteasome system. Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment., Competing Interests: The authors declare no conflict of interest.

Objectives: The aim of this study was to investigate primary care managers' perceptions of their capability in providing care planning to patients with complex needs. Care planning is defined as a process where the patient, family and health professionals engage in dialogue about the patient's care needs and plan care interventions together., Methods: Semi-structured interviews with 18 primary care managers in western Sweden were conducted using Westrin's theoretical cooperation model. Data were analysed using a qualitative deductive method., Main Findings: Results reveal that the managers' approach to care planning was dominated by non-cooperation and separation. The managers were permeated by uncertainty about the meaning of the task of care planning as such. They did not seem to be familiar with the national legislation stipulating that every healthcare provider must meet patients' need for care interventions and participate in the care planning., Implications for Practice: To accomplish care planning, the process needs to cross - and overcome - both professional and organisational boundaries. There is also a need for incentives to develop working methods that promote local cooperation in order to facilitate optimal care for patients with complex needs., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-γ-induced expression of p27(Kip1) (p27) repressed Myc's activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and sufficient for IFN-γ-induced turnover of Myc. p27 interacted with Myc in the nucleus involving the C-termini of the two proteins, including Myc box 4 of Myc. The C-terminus but not the Cdk2 binding fragment of p27 was sufficient for inducing Myc degradation. Protein expression data of The Cancer Genome Atlas breast invasive carcinoma set revealed significantly lower Myc protein levels in tumors with highly expressed p27 lacking phosphorylation at Thr-157--a marker for active p27 localized in the nucleus. Further, these conditions correlated with favorable tumor stage and patient outcome. This novel regulation of Myc by IFN-γ/p27(KIP1) potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.

There is a great interest in finding ways to inhibit the expression or activity of the "undruggable" MYC, a master regulator of transcription and one of the most deadly oncoproteins in human cancer. In this issue of Cancer Discovery, Wiegering and colleagues find a way of inhibiting translation of MYC in colorectal cancer cells by directly targeting the translation initiation factor eIF4A, resulting in inhibition of MYC-dependent proliferation of colorectal tumor cells in vitro and in vivo., (©2015 American Association for Cancer Research.)

Background: Chronic bronchitis is related to worse general health status, exacerbations and mortality among subjects with COPD. Also less longstanding cough and phlegm may be related to worse prognosis in COPD but this has rarely been evaluated in population-based studies., Aim: To evaluate the relationship between productive cough, exacerbations and mortality among subjects with and without COPD., Method: All subjects with COPD (n = 993) were identified together with sex- and age matched reference subjects without obstructive lung function impairment from four population-based cohorts in 2002-04. Baseline spirometry and structured interview including data on exacerbations last 12 months were used in this study (n = 1986) together with mortality data collected until February 2012., Results: Productive cough was more common in COPD than non-COPD (42.8 vs. 23.5%, p < 0.001), more common in men than women, but associated to exacerbations in both sexes. COPD-subjects with productive cough had the highest risk for exacerbations in both sexes and they had a significantly increased risk for death (HR 1.48, 95% CI 1.13-1.94) also when adjusted for sex, age, BMI, smoking habits and heart disease., Conclusion: Productive cough was common and increased the risk for exacerbations in both sexes, in both COPD and non-COPD. COPD-subjects with productive cough had the highest risk for exacerbations and a significantly higher risk for death also after adjustment for common risk factors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence, a major barrier imposed on tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAF(V600E)-induced senescence in vitro. However, it is still unclear whether MYC has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAF(V600E) and tamoxifen-regulatable MycER, we show that tamoxifen-induced activation of MYC accelerated the onset and increased the number and size of BRAF(V600E)-driven adenomas in a dose-dependent manner, resulting in reduced survival. Furthermore, MYC activation leads to reduced expression of the senescence markers p16(INK4A), p21(CIP1), and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67(+) tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAF(V600E)-induced senescence-like state. Initial activation of MYC followed by tamoxifen withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16(INK4A) and p21(CIP1), and reduced number of Ki67(+) cells, indicating that MYC inactivation restores BRAF(V600E)-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process, with implications for future treatment strategies., (©2014 American Association for Cancer Research.)

Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd-Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCF(FBXO28) activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCF(FBXO28) plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer., (© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Studies in primary and tumor cells suggest that MYC plays an important role in regulating cellular senescence, thereby impacting on tumor development. Here we describe different common methods to measure senescence in cell cultures and in tissues. These include measurement of senescence-associated β-galactosidase activity (SA-β-gal), senescence-associated heterochromatin foci (SAHFs), proliferative arrest, morphological changes, and expression and activity of proteins involved in the senescence process, such as p53 and Rb pathway proteins and secretory proteins. It is important to note that there is no unique marker that unambiguously defines a senescent state, and it is therefore necessary to combine measurements of several different markers that together determine whether cells are senescent or not. Measurement of senescence is an important aspect of studies of MYC biology and will improve our understanding of MYC function and regulation both in preclinical and clinical settings. This may form the basis for new concepts of pro-senescence therapy to combat MYC in cancer.

Aim: To elucidate registered nurses' experiences of coordinated care planning in outpatient care., Background: Coordinated care planning has been studied from the perspectives of both patients and nurses in inpatient care, but it is deficient in outpatient care., Method: Qualitative content analysis of interviews with 10 registered nurses participating in two focus groups., Results: An overall theme was identified: creating concordant communication in relation to patient and health-care providers. The result is based on four categories and nine subcategories., Conclusions: Nurses need extraordinary communication skills to reach concordance in outpatient care planning. In addition to involving and supporting the patients and next of kin in the decision-making process, the outcome of the nursing process must be understood by colleagues and members of other professions and health-care providers (non-nursing)., Implications for Nursing Management: An effective outpatient care-planning process requires that care managers understand the impact of communicating, transferring information and reaching consensus with other health-care providers, actively supporting employees in the outpatient care-planning process and contributing to the development of common goals and policy documents across organisational boundaries., (© 2012 Blackwell Publishing Ltd.)

Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.

Background: The poor recognition and related underdiagnosis of COPD contributes to an underestimation of mortality in subjects with COPD. Data derived from population studies can advance our understanding of the true burden of COPD. The objective of this report was to evaluate the impact of COPD on mortality and its predictors in a cohort of subjects with and without COPD recruited during the twenty first century., Methods: All subjects with COPD (n = 993) defined according to the GOLD spirometric criteria, FEV1/FVC < 0.70, and gender- and age-matched subjects without airway obstruction, non-COPD (n = 993), were identified in a clinical follow-up survey of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies cohorts in 2002-2004. Mortality was observed until the end of year 2007. Baseline data from examination at recruitment were used in the risk factor analyses; age, smoking status, lung function (FEV1 % predicted) and reported heart disease., Results: The mortality was significantly higher among subjects with COPD, 10.9%, compared to subjects without COPD, 5.8% (p < 0.001). Mortality was associated with higher age, being a current smoker, male gender, and COPD. Replacing COPD with FEV1 % predicted in the multivariate model resulted in the decreasing level of FEV1 being a significant risk factor for death, while heart disease was not a significant risk factor for death in any of the models., Conclusions: In this cohort COPD and decreased FEV1 were significant risk factors for death when adjusted for age, gender, smoking habits and reported heart disease.

Myc plays an important role in tumor development, including acute myeloid leukemia (AML). However, MYC is also a powerful inducer of apoptosis, which is one of the major failsafe programs to prevent cancer development. To clarify the relative importance of the extrinsic (death receptor-mediated) versus the intrinsic (mitochondrial) pathway of apoptosis in MYC-driven AML, we coexpressed MYC together with anti-apoptotic proteins of relevance for AML; BCL-X(L)/BCL-2 (inhibiting the intrinsic pathway) or FLIP(L) (inhibiting the extrinsic pathway), in hematopoietic stems cells (HSCs). Transplantation of HSCs expressing MYC into syngeneic recipient mice resulted in development of AML and T-cell lymphomas within 7-9 weeks as expected. Importantly, coexpression of MYC together with BCL-X(L)/BCL-2 resulted in strongly accelerated kinetics and favored tumor development towards aggressive AML. In contrast, coexpression of MYC and FLIP(L) did neither accelerate tumorigenesis nor change the ratio of AML versus T-cell lymphoma. However, a change in distribution of immature CD4(+)CD8(+) versus mature CD4(+) T-cell lymphoma was observed in MYC/FLIP(L) mice, possibly as a result of increased survival of the CD4+ population, but this did not significantly affect the outcome of the disease. In conclusion, our findings provide direct evidence that BCL-X(L) and BCL-2 but not FLIP(L) acts in synergy with MYC to drive AML development.

Background: A relationship between local and systemic inflammation and different co-morbidities, such as cardiovascular, has been discussed in relation to disease process and prognosis in COPD., Aim: To evaluate if conditions as cardiovascular diseases, diabetes, chronic rhinitis and gastroesophageal reflux are overrepresented in COPD., Methods: All subjects with COPD according to GOLD, FEV(1)/FVC<0.70, were identified (n = 993) from the clinical follow-up in 2002-04 of the OLIN (Obstructive Lung Disease in Northern Sweden) studies' cohorts together with 993 gender- and age-matched reference subjects without COPD (non-COPD, further divided into normal and restrictive lung function). Interview data on co-morbidity and symptoms were used., Results: Cardiovascular co-morbidity, taken together heart disease, hypertension, stroke and intermittent claudication, was the most common and higher in COPD compared to in normal lung function (Nlf) 50.1% vs 41.0% (p<0.001). The prevalence of chronic rhinitis and gastroesophageal reflux (GERD) was higher in COPD compared to in Nlf (43.1% vs 32.3%, p<0.001 and 16.7% vs 12.0%, p = 0.011). In restrictive lung function the prevalence of chronic rhinitis, cardiovascular disease, hyperlipemia and diabetes was higher compared to in Nlf (41.0% vs 32.3%, p = 0.017, 59.0% vs 41.0%, p<0.001, 29.2% vs.12.9%, p = 0.033, 20.9% vs 8.6%, p <0.001). In COPD and heart disease, 62.5% had chronic rhinitis and/or GERD, while in Nlf the corresponding proportion was 42.5%., Conclusion: Co-morbid conditions such as cardiovascular disease, chronic rhinitis and gastroesophageal reflux were common in COPD. The overlap between heart disease, chronic rhinitis and GERD was large in COPD. Restrictive lung function did also identify a population with increased disease burden.

Data accumulating during the last two decades suggest that tumorigenesis is held in check by two major intrinsic failsafe mechanisms; apoptosis and cellular senescence. While apoptosis is a programmed cell death process, cellular senescence, which is the focus of this article, is defined as irreversible cell cycle arrest. This process is triggered either by telomere erosion or by acute stress signals including oncogenic stress induced by overactive oncogenes or underactive tumor suppressor genes. The outcome of this is often replication overload and oxidative stress resulting in DNA damage. Oncogenic stress induces at least three intrinsic pathways, p16/pRb-, Arf/p53/p21- and the DNA damage response (DDR)-pathways, that induce premature senescence if the stress exceeds a threshold level. Oncogene-induced senescence (OIS) is frequently observed in premalignant lesions both in animal tumor models and in human patients but is essentially absent in advanced cancers, suggesting that malignant tumor cells have found ways to bypass or escape senescence. This review focuses on cell-autonomous mechanism by which certain oncogenes, tumor suppressor genes and components of the DDR/DNA-repair machinery suppress senescence - mechanisms that are exploited by tumor cells to evade senescence and continue to multiply. In this way, tumor cells become addicted to the continuous activity of senescence suppressor proteins. However, some senescence pathways, although under suppression, may remain intact and can be re-established if senescence suppressor proteins are inactivated or if senescence inducers are reactivated. This can hopefully form the basis for a "pro-senescence therapy" strategy to combat cancer in the future., (Copyright © 2011 Elsevier Ltd. All rights reserved.)