Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.

Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression.

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and ß1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.

Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth.

The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic.

IDH2 reprograms mitochondrial dynamics in cancer through a HIF-1α-regulated pseudohypoxic state.

The role of mitochondria in cancer continues to be debated and paradoxically implicated in opposing functions in tumor growth and tumor suppression. To understand this dichotomy, we explored the function of mitochondrial isocitrate dehydrogenase (IDH)2, a tricarboxylic acid cycle enzyme mutated in subsets of acute leukemias and gliomas, in cancer. Silencing of IDH2 in prostate cancer cells impaired oxidative bioenergetics, elevated reactive oxygen species (ROS) production, and promoted exaggerated mitochondrial dynamics. This was associated with increased subcellular mitochondrial trafficking, turnover of membrane focal adhesion complexes, and enhanced tumor cell migration and invasion, without changes in cell cycle progression. Mechanistically, loss of IDH2 caused ROS-dependent stabilization of hypoxia-inducible factor-1α in normoxia, which was required for increased mitochondrial trafficking and tumor cell movements. Therefore, IDH2 is a dual regulator of cancer bioenergetics and tumor cell motility. This pathway may reprogram mitochondrial dynamics to differentially adjust energy production or promote tumor cell invasion in response to microenvironment conditions.-Wang, Y., Agarwal, E., Bertolini, I., Ghosh, J. C., Seo, J. H., Altieri, D. C. IDH2 reprograms mitochondrial dynamics in cancer through a HIF-1α-regulated pseudohypoxic state.

Feasibility of using the "modified NUTrition Risk In the Critically ill" nutritional risk screening tool to identify nutritionally at-risk patients in an Australian intensive care unit.

BACKGROUND: The modified NUTrition Risk In the Critically ill (mNUTRIC) score has been demonstrated to accurately quantify the risk of negative patient outcomes and discriminate which patients will benefit the most from nutrition intervention in an intensive care unit (ICU) setting. Calculation of an mNUTRIC score, however, may be time-intensive and unable to be performed within available resources. This may prevent high-risk patients from being identified and reviewed by a dietitian. OBJECTIVES: The purpose of this study was to assess the feasibility of using the mNUTRIC tool to screen for patients at increased nutrition risk and to determine the proportion of those high-risk patients who were reviewed by a dietitian. SUBJECTS/METHODS: A retrospective observational study of 260 critically ill patients was conducted between 01/01/2017 and 30/05/2017 in a 20-bed Australian tertiary ICU. Participants included all adults admitted to the ICU for more than 72 h. Feasible implementation was defined as calculating an mNUTRIC score in <5 min per patient where all data were available for >90% of patients. RESULTS: A median time of 4 min and 54 s (interquartile range: 4.3-5.6 min) was required to calculate each mNUTRIC score, with 96% of scores calculated in <10 min. Data were available to calculate mNUTRIC scores for 93% (241/260) of patients. The mNUTRIC tool identified 81 patients at high nutrition risk, 44% (36/81) of whom were not reviewed by a dietitian. There were 21 high-risk patients who were purposefully excluded from dietetic review for various clinical reasons, leaving 15 high-risk patients (19%) who were not reviewed by a dietitian. CONCLUSIONS: Implementation of the mNUTRIC tool was not feasible in our ICU, given the set dietetic resources (0.6 full-time equivalent). Shared responsibility of nutrition screening or automating the calculation may be possible solutions to increase feasibility of mNUTRIC screening.

An investigation into the nutritional status of patients receiving an Enhanced Recovery After Surgery (ERAS) protocol versus standard care following Oesophagectomy.

PURPOSE: Enhanced Recovery After Surgery (ERAS) protocols have been effectively expanded to various surgical specialities including oesophagectomy. Despite nutrition being a key component, actual nutrition outcomes and specific guidelines are lacking. This cohort comparison study aims to compare nutritional status and adherence during implementation of a standardised post-operative nutritional support protocol, as part of ERAS, compared to those who received usual care. METHODS: Two groups of patients undergoing resection of oesophageal cancer were studied. Group 1 (n = 17) underwent oesophagectomy between Oct 2014 and Nov 2016 during implementation of an ERAS protocol. Patients in group 2 (n = 16) underwent oesophagectomy between Jan 2011 and Dec 2012 prior to the implementation of ERAS. Demographic, nutritional status, dietary intake and adherence data were collected. Ordinal data was analysed using independent t tests, and categorical data using chi-square tests. RESULTS: There was no significant difference in nutrition status, dietary intake or length of stay following implementation of an ERAS protocol. Malnutrition remained prevalent in both groups at day 42 post surgery (n = 10, 83% usual care; and n = 9, 60% ERAS). A significant difference was demonstrated in adherence with earlier initiation of oral free fluids (p <0.008), transition to soft diet (p <0.004) and continuation of jejunostomy feeds on discharge (p <0.000) for the ERAS group. CONCLUSION: A standardised post-operative nutrition protocol, within an ERAS framework, results in earlier transition to oral intake; however, malnutrition remains prevalent post surgery. Further large-scale studies are warranted to examine individualised decision-making regarding nutrition support within an ERAS protocol.

Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.

BACKGROUND: There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFß/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival. METHODS: IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant. RESULTS: We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors. CONCLUSION: The identification of these 2 novel mechanisms leading to induction of cell death indicates MK-2206 might be a potential clinical candidate for therapeutic targeting of the subset of IGF1R-dependent cancers in CRC.

Treatment Adherence and Adherence Patterns of Tofacitinib and Self-Injectable TNFi Use in People with Rheumatoid Arthritis.

OBJECTIVE: To assess tofacitinib and self-injectable tumor necrosis factor inhibitor (TNFi) adherence using the Medication Event Monitoring System (MEMS) and characterize association with adherence in patients with rheumatoid arthritis (RA). METHODS: Eligible patients were enrolled from the Forward Databank within 6 months of initiating tofacitinib or injectable TNFi or from participating clinics where these were first prescribed. MEMS caps and patient diaries were used to compile dosing over 9 months. Demographics and disease characteristics were collected every 6 months, and the Beliefs about Medicines Questionnaire only at baseline. Adherence along with its components, initiation, implementation, and persistence, were calculated. RESULTS: Of the 112 consented to participate, 82 (73%) remained in the final analysis with recruitment from clinics 47 (57%) and Forward 35 (43%). Sixty-two (76%) initiated tofacitinib with 87% taking it quaque die and twenty (24%) TNFi. At 9 months, 77% of tofacitinib were persistent versus 70% for TNFi (P = 0.65), and implementation was similar (0.84 vs. 0.82; P = 0.57). In multivariable models, increased baseline patient global assessment was consistently associated with discontinuation (hazard ratio 1.31 [1.07-1.61]). There was increased adherence to methotrexate (MTX) when taking tofacitinib that led to higher combined adherence for tofacitinib than TNFi (0.81 vs. 0.69; P = 0.03), but no significant differences remained in multivariable models. In sensitivity analysis, consistent morning intake for tofacitinib and evening intake for MTX was associated with improved adherence. CONCLUSION: We found no statistical differences in adherence between patients with RA initiating tofacitinib and self-injectable TNFi, although 15% to 30% were nonadherent. Concomitant MTX, patient global assessment, and a consistent time of day intake were associated with adherence.

Clinical and Electrophysiological Factors Predicting Prolonged Recovery in Children with Guillain-Barré Syndrome.

OBJECTIVE: To compare clinical and nerve conduction studies (NCS) parameters predictive of outcome in children with acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). METHODS: In this prospective observational study, NCS was done on all children at admission and repeated before discharge. Functional status of patients was graded as per Hughes Disability score. These children were followed up till they achieved independent walking. Clinical and NCS criteria were compared between (a) AMAN and AIDP and (b) two subgroups of children with AMAN-those who achieved early (within 60 d) versus delayed (i.e., after 60 d) walking. RESULTS: Fifty-seven children were initially enrolled, first NCS showed inexcitable nerves in 10, AMAN in 29, acute motor-sensory axonal neuropathy (AMSAN) in 3, AIDP in 13, and 2 were normal. Subsequent NCS showed AMAN in 37, AIDP in 15, AMSAN in 3 patients. There were no deaths, 16 required ventilation. Follow-up till independent walking, was available for 40 patients. AMAN was associated with faster progression, greater peak disability, prolonged hospital stay, and delayed walking (p < 0.05). Asymmetrical nerve involvement predicted prolonged hospital stay as well as delayed walking. In the AMAN group, prolonged ulnar F-wave latencies were significantly associated with delayed walking (p = 0.02). CONCLUSION: Long term prognosis of pediatric GBS is generally satisfactory. AMAN, asymmetric involvement and prolonged ulnar F-wave latencies in children with AMAN were associated with delayed walking.

Changes in Disease-Modifying Antirheumatic Drug Treatment for Patients With Rheumatoid Arthritis in the US During the COVID-19 Pandemic: A Three-Month Observational Study.

OBJECTIVE: To understand medication, lifestyle, and clinical care changes of persons with rheumatoid arthritis (RA) during the first months (March 2020 through May 2020) of the COVID-19 pandemic in the US. METHODS: Data were collected from adults with RA participating in FORWARD, The National Databank for Rheumatic Diseases observational registry, who answered COVID-19 web-based surveys in May 2020 and previously provided baseline characteristics and medication use prior to the US COVID-19 pandemic. We compared medication changes by disease-modifying antirheumatic drug (DMARD) exposure in logistic models that were adjusted for age, sex, comorbidities including pulmonary and cardiovascular diseases, education level, health insurance status, RA disease activity, fatigue, and polysymptomatic distress. RESULTS: Of 734 respondents, 221 (30%) reported medication changes. Among respondents who experienced a medication change, i.e., "medication changers/changers," glucocorticoids (GCs) were more commonly used compared to respondents who did not experience a medication change ("non-changers") (33% versus 18%). Non-hydroxychloroquine conventional DMARDs were less commonly used in changers compared to non-changers pre-COVID-19 (49% versus 62%), and changers reported more economic hardship during the COVID-19 pandemic compared to non-changers (23% versus 15%). While JAK inhibitor use was associated with the likelihood of a medication change, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.0, 3.4), only pre-COVID GC use remained a strong predictor for medication change in multivariable models (OR 3.0 [95% CI 1.9, 4.9]). Change in care was observed to have a significant association with pulmonary disease (OR 2.9 [95% CI 1.3, 6.5]), worse RA disease activity (OR 1.1 [95% CI 1.0, 1.1]), and GC use (OR 1.6 [95% CI 1.0, 2.5]). While the incidence of medication changes was the same before and after the American College of Rheumatology (ACR) guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic were first published in April 2020, self-imposed changes in medication were approximately twice as likely before publication of the guidelines, and physician-guided changes were more likely after publication. CONCLUSION: Persons with RA in the US made substantial medication changes during the first three months of the COVID-19 pandemic, and changes among persons with RA after publication of the ACR guidance in April 2020 were made with increased physician guidance.

Ward-based nutrition care practices and a snapshot of patient care: Results from nutritionDay in the ICU.

BACKGROUND: Poor adherence to intensive care unit (ICU) guidelines is common, leading to suboptimal nutritional care. This study determined current ward-based nutrition care practices in the Indian ICU setting, comparing them to international best-practice guidelines and provided patient demographic, clinical and nutritional information to serve as baseline data for future benchmarking. METHODS: This multi-site cross-sectional retrospective study analysed data collected from nutritionDay worldwide audits (2012-2016) across ICUs from a chain of urban private hospitals in India. Additional guideline-specific data were collected through questionnaires and phone interviews with the Head of Dietetics Departments in the participating hospitals. RESULTS: Overall, 10 ICUs and 457 participants were included. It was common practice to use modified versions of the Mini Nutritional Assessment-Short Form (MNA-SF) and Subjective Global Assessment (SGA) for nutrition screening and assessment. Nearly half the participants (n = 222, 49%) received nutrition orally. A majority of the remaining participants received enteral nutrition (n = 163, 36%) or no nutrition (n = 60, 13%) at the time of data collection. The calories prescribed for most participants were between 1500 and 1999 kilocalories per day (n = 207, 45%), with no nutrition planned for 115 (25%) participants. Three-quarters (n = 129, 74%) of participants on EN received the planned calories, while 24% (n = 42) were given less than planned. CONCLUSION: Overall, most participants received the calories planned for enteral nutrition. The use of modified screening and assessment tools and suboptimal delivery of EN remains a global problem for critical care, possibly requiring a more pragmatic approach to nutritional therapy.

Prevalence of malnutrition risk and poor food intake in older adults in Indian hospitals: A prospective observational nutritionDay study with novel mapping of malnutrition risk to the Malnutrition Screening Tool.

AIM: Current literature regarding the prevalence and consequences of poor dietary intake and risk of malnutrition in older adults is limited to wealthier regions including the United States, Europe and Australasia. With a rapidly ageing population in India, this prospective observational study aimed to evaluate hospital food intake and malnutrition risk and their impact on hospital length of stay, readmission rates and in-hospital mortality of older adults in Indian hospitals. METHODS: Data collected during nutritionDay worldwide audits (2014-2016), in five urban, private hospitals in India included baseline demographic and clinical data on patients aged ≥60 years. Proportion of food consumed at one main meal was recorded and data on length of stay, readmissions and in-hospital mortality were collected 30 days post-baseline. RESULTS: A total of 262 participants (mean age: 69 ± 8 years; 65% males) were recruited. Mapped malnutrition risk (mapped Malnutrition Screening Tool [mMST] score ≥ 2) on admission was 31% and increased to 44% during the course of hospitalisation. Over one quarter of participants consumed ≤50% of their meal (28%). Over half the participants were found to be eating poorly (59%) and those identified as at risk of malnutrition were not offered additional nutrition support. The median LOS was 8 days (range: 1-92), 30-day readmission rates were 7% and in-hospital mortality was 0.4%. Malnutrition risk and poor food intake were not associated with health-related outcomes. CONCLUSION: Older adults in Indian acute care hospitals have a noticeable prevalence of malnutrition risk and poor food intake. There is an opportunity for future research to focus on identifying and managing nutritional issues.

A Clinical Study to Evaluate the Association Between Metabolic Syndrome and Sensorineural Hearing Loss.

Metabolic syndrome is considered to be a triggering factor for deterioration of health related quality of life. In present study we assessed hearing loss consequent to metabolic syndrome. A total of 100 patients diagnosed for metabolic syndrome (IDF criteria) were included in the study. All the patients underwent pure tone audiometry and impedance audiometry. All the patients underwent anthropometric measurements, lipid profile, blood sugar and blood pressure assessments. Data was analyzed using SPSS 21.0 software. A total of 62% patients had sensorineural hearing loss. Maximum (35%) had mild hearing loss, followed by moderate hearing loss (23%). Only 4 (4%) cases had severe hearing loss. Older age, wider waist circumference, higher fasting blood glucose levels and lower blood pressure were found to be significantly associated with sensorineural hearing loss and its severity on univariate analysis. However, on multivariate assessment only age and waist circumference showed a significant association with hearing loss.

Significant treatment gap and co-morbidities identified in an epidemiological survey of pediatric epilepsy in rural suburbs of India.

PURPOSE: A cross-sectional epidemiological survey of children was conducted in two rural clusters to estimate the point prevalence and study various aspects of childhood epilepsy. MATERIAL AND METHODS: In the first stage, a house-to-house survey was conducted by health workers using a screening questionnaire, which was pre-validated in a pilot study. All screen positive houses were visited by pediatric neurologist for detailed evaluation. Children with a clinical diagnosis of epilepsy underwent EEG and were evaluated for type of seizure, epilepsy syndrome, etiology, co-morbidities and treatment gap. Knowledge, attitude and practice regarding epilepsy was assessed amongst caregivers of the affected children. RESULTS: A total population of 75,455 population was screened, 19,181 children aged 2 months to 18 years were identified. Out of 355 screen positive children, 66 were diagnosed with epilepsy. The point prevalence of pediatric epilepsy was 3.44 per 1000 children. 53% had focal epilepsy, 31.8% had an identifiable epilepsy syndrome, 44% had at least one comorbidity. The etiology was identified in 68%, the commonest being perinatal brain insult. The magnitude of treatment gap was 45.45%, with significant deficits in knowledge. CONCLUSION: There are significant deficits in diagnosis and treatment of pediatric epilepsy among the rural population of India. The existing rural health care facilities need to be augmented to facilitate the timely diagnosis and optimum care of these children, including care of associated co-morbidities.

A cancer ubiquitome landscape identifies metabolic reprogramming as target of Parkin tumor suppression.

Changes in metabolism that affect mitochondrial and glycolytic networks are hallmarks of cancer, but their impact in disease is still elusive. Using global proteomics and ubiquitome screens, we now show that Parkin, an E3 ubiquitin ligase and key effector of mitophagy altered in Parkinson's disease, shuts off mitochondrial dynamics and inhibits the non-oxidative phase of the pentose phosphate pathway. This blocks tumor cell movements, creates metabolic and oxidative stress, and inhibits primary and metastatic tumor growth. Uniformly down-regulated in cancer patients, Parkin tumor suppression requires its E3 ligase function, is reversed by antioxidants, and is independent of mitophagy. These data demonstrate that cancer metabolic networks are potent oncogenes directly targeted by endogenous tumor suppression.

Nutrition risk and mortality in older oncology patients: An exploratory study.

AIM: The primary aim of this analysis was to identify if two standard measures incorporated into the comprehensive geriatric assessment; specifically, malnutrition risk and body mass index (BMI), could predict 12-month mortality in older patients with solid tumours. The secondary aim was to evaluate if malnutrition risk and BMI were associated with chemotherapy outcomes (discontinuation/modification of treatment) in older patients with solid tumours. METHODS: Older patients (aged ≥70 years) with solid cancers were recruited from the outpatient oncology clinic of a tertiary hospital in Brisbane, Australia. Participants' nutritional parameters, BMI, and malnutrition risk (determined using the Malnutrition Screening Tool (MST)) were recorded at baseline. Mortality data and chemotherapy outcomes were recorded for 12 months. RESULTS: Seventy-four participants (67% males, median age 77 (±4.4) years) were recruited. Nearly half the cohort was at-risk of malnutrition at baseline (n = 39, 46%). Chemotherapy was prescribed to 39% (n = 29) of the cohort. For patients receiving chemotherapy neither being underweight nor having a low or medium risk of malnutrition was associated with adverse chemotherapy outcomes or 12-month mortality. At a bivariate level, malnutrition risk was significantly associated with 12-month mortality in patients who did not receive chemotherapy (P = 0.018), but not BMI. CONCLUSIONS: This analysis indicates that malnutrition risk was a potential indicator of 12-month mortality in cases where chemotherapy was considered unfeasible. However, this was not an independent risk factor. Further investigation using a larger sample is required to determine the association between malnutrition risk, quality of life and mortality in patients who are not considered to be fit for chemotherapy.

The αvß6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis.

Prostate cancer (PrCa) cells crosstalk with the tumour microenvironment by releasing small extracellular vesicles (sEVs). sEVs, as well as large extracellular vesicles (LEVs), isolated via iodixanol density gradients from PrCa cell culture media, express the epithelial-specific αvß6 integrin, which is known to be induced in cancer. In this study, we show sEV-mediated protein transfer of αvß6 integrin to microvascular endothelial cells (human microvascular endothelial cells 1 - HMEC1) and demonstrate that de novo αvß6 integrin expression is not caused by increased mRNA levels. Incubation of HMEC1 with sEVs isolated from PrCa PC3 cells that express the αvß6 integrin results in a highly significant increase in the number of nodes, junctions and tubules. In contrast, incubation of HMEC1 with sEVs isolated from ß6 negative PC3 cells, generated by shRNA against ß6, results in a reduction in the number of nodes, junctions and tubules, a decrease in survivin levels and an increase in a negative regulator of angiogenesis, pSTAT1. Furthermore, treatment of HMEC1 with sEVs generated by CRISPR/Cas9-mediated down-regulation of ß6, causes up-regulation of pSTAT1. Overall, our findings suggest that αvß6 integrin in cancer sEVs regulates angiogenesis during PrCa progression.

The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells.

Mitochondria are signaling hubs in eukaryotic cells. Here, we showed that the mitochondrial FUN14 domain-containing protein-1 (FUNDC1), an effector of Parkin-independent mitophagy, also participates in cellular plasticity by sustaining oxidative bioenergetics, buffering ROS production, and supporting cell proliferation. Targeting this pathway in cancer cells suppressed tumor growth but rendered transformed cells more motile and invasive in a manner dependent on ROS-mediated mitochondrial dynamics and mitochondrial repositioning to the cortical cytoskeleton. Global metabolomics and proteomics profiling identified a FUNDC1 interactome at the mitochondrial inner membrane, comprising the AAA+ protease, LonP1, and subunits of oxidative phosphorylation, complex V (ATP synthase). Independently of its previously identified role in mitophagy, FUNDC1 enabled LonP1 proteostasis, which in turn preserved complex V function and decreased ROS generation. Therefore, mitochondrial reprogramming by a FUNDC1-LonP1 axis controls tumor cell plasticity by switching between proliferative and invasive states in cancer.

Correction: Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.

[This corrects the article DOI: 10.18632/oncotarget.23749.].

Real-World Adherence to Oral Methotrexate Measured Electronically in Patients With Established Rheumatoid Arthritis.

OBJECTIVE: To assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA). METHODS: Eligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression. RESULTS: Overall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease-modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD-experienced versus biologic DMARD-naïve patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89). CONCLUSION: Even in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.