PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.

Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators.

Programmed ferroptotic death eliminates cells in all major organs and tissues with imbalanced redox metabolism due to overwhelming iron-catalyzed lipid peroxidation under insufficient control by thiols (Glutathione (GSH)). Ferroptosis has been associated with the pathogenesis of major chronic degenerative diseases and acute injuries of the brain, cardiovascular system, liver, kidneys, and other organs, and its manipulation offers a promising new strategy for anticancer therapy. This explains the high interest in designing new small-molecule-specific inhibitors against ferroptosis. Given the role of 15-lipoxygenase (15LOX) association with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) in initiating ferroptosis-specific peroxidation of polyunsaturated PE, we propose a strategy of discovering antiferroptotic agents as inhibitors of the 15LOX/PEBP1 catalytic complex rather than 15LOX alone. Here we designed, synthesized, and tested a customized library of 26 compounds using biochemical, molecular, and cell biology models along with redox lipidomic and computational analyses. We selected two lead compounds, FerroLOXIN-1 and 2, which effectively suppressed ferroptosis in vitro and in vivo without affecting the biosynthesis of pro-/anti-inflammatory lipid mediators in vivo. The effectiveness of these lead compounds is not due to radical scavenging or iron-chelation but results from their specific mechanisms of interaction with the 15LOX-2/PEBP1 complex, which either alters the binding pose of the substrate [eicosatetraenoyl-PE (ETE-PE)] in a nonproductive way or blocks the predominant oxygen channel thus preventing the catalysis of ETE-PE peroxidation. Our successful strategy may be adapted to the design of additional chemical libraries to reveal new ferroptosis-targeting therapeutic modalities.

A novel XPA splice-site mutation identified in a 4-year-old Filipino girl with xeroderma pigmentosum.

We herein report a case of a 4-year-old Filipino girl initially seen through online consultation from a general physician. She was born to a 22-year-old primigravid mother, with no birth complications nor a history of consanguinity in the family. During the 1st month of life, she developed hyperpigmented macules over the face, neck, upper back, and limbs, which were exacerbated by sun exposure. At 2 years old, she developed a solitary erythematous papule on the nasal area, which gradually enlarged within one year and developed into an exophytic ulcerating tumor extending to the right supra-alar crease. Xeroderma pigmentosum and squamous cell carcinoma were confirmed by whole-exome sequencing and skin biopsy, respectively.

Correlation of amyloid and ameloblast-associated proteins to odontogenic cysts and tumors: A cross-sectional study.

Background and Aims: Odontogenic cysts and tumors often form hard and soft structures that resemble odontogenesis. It is well known that amyloid is produced in Pindborg tumors; however, it is still debatable whether it is also formed in other odontogenic tumors and cysts. This study aimed to detect the presence of amyloid in different odontogenic cysts and tumors in correlation to matrix proteins secreted during enamel formation; namely amelogenin and odontogenic ameloblast-associated protein. Methods: This study included formalin fixed paraffin embedded tissue blocks of 106 different types of odontogenic cysts and tumors. Congo red and thioflavin T were performed to confirm the presence of amyloid; immunohistochemistry was used to detect amelogenin and odontogenic ameloblast-associated protein. Results: Amyloid was detected in pindborg tumors (conventional), adenomatoid odontogenic tumors, odontogenic fibroma (Amyloid variant), follicular solid and unicystic ameloblastomas, radicular cysts, dentigerous cysts, dentinogenic ghost cell odontogenic tumor, ameloblastic fibroma, calcifying odontogenic cyst, and primordial Odontogenic tumor. Amelogenin was detected in 95.3% of the cases, while odontogenic ameloblast-associated protein was detected in 93.4% of the cases. The association between odontogenic ameloblast-associated protein and amyloid was highly significant at p < 0.01. However, there was no significant relationship between amelogenin and amyloid p > 0.05. Conclusion: Although pindborg tumor is the bonafide example of amyloid deposition in odontogenic tumors, this study concluded that amyloid may be deposited in traces to massive amounts in various odontogenic cysts and tumors, and it is significantly linked to odontogenic ameloblast-associated protein but not amelogenin matrix protein, since all amyloid cases were odontogenic ameloblast associated protein positive.

SMOFlipid Impact on Growth and Neonatal Morbidities in Very Preterm Infants.

The soybean oil, medium-chain triglycerides, olive oil, and fish oil lipid (SMOFlipid) is increasingly being used worldwide without definite evidence of its benefits. We examined the effect of SMOFlipid on growth velocity and neonatal morbidities in very preterm infants. Very preterm infants who received soybean-based lipid emulsion between January 2015 and 2018 were compared with those who received SMOFlipids between 2019 and January 2022 in our neonatal tertiary center. Linear regression analysis was conducted to analyze the association between type of lipid emulsion and growth velocity. Modified log-Poisson regression with generalized linear models and a robust variance estimator (Huber−White) were applied to adjust for potential confounding factors. A total of 858 infants met our inclusion criteria. Of them, 238 (27.7%) received SMOFlipid. SMOFlipid was associated with lower growth velocity between birth and 36-week corrected gestational age compared with intralipid Δ weight z-score (adjusted mean difference (aMD) −0.67; 95% CI −0.69, −0.39). Subgroup analysis indicated that mainly male infants in the SMOFlipid−LE group had a lower Δ weight z-score compared to those in the intralipid group (p < 0.001), with no difference observed in females (p = 0.82). SMOFlipid was associated with a lower rate of bronchopulmonary dysplasia (BPD) (aRR 0.61; 95% CI 0.46, 0.8) and higher rate of late-onset sepsis compared with intralipid (aRR 1.44; 95% CI 1.22−1.69). SMOFlipid was associated with lower growth velocity and BPD but higher rate of late-onset sepsis­it is a double-edged sword.

P. aeruginosa augments irradiation injury via 15-lipoxygenase-catalyzed generation of 15-HpETE-PE and induction of theft-ferroptosis.

Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells, causing their death and inducing a state of immunodeficiency combined with intestinal dysbiosis and nonproductive immune responses. We found enhanced Pseudomonas aeruginosa (PAO1) colonization of the gut leading to host cell death and strikingly decreased survival of irradiated mice. The PAO1-driven pathogenic mechanism includes theft-ferroptosis realized via (a) curbing of the host antiferroptotic system, GSH/GPx4, and (b) employing bacterial 15-lipoxygenase to generate proferroptotic signal - 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) - in the intestines of irradiated and PAO1-infected mice. Global redox phospholipidomics of the ileum revealed that lysophospholipids and oxidized phospholipids, particularly oxidized phosphatidylethanolamine (PEox), represented the major factors that contributed to the pathogenic changes induced by total body irradiation and infection by PAO1. A lipoxygenase inhibitor, baicalein, significantly attenuated animal lethality, PAO1 colonization, intestinal epithelial cell death, and generation of ferroptotic PEox signals. Opportunistic PAO1 mechanisms included stimulation of the antiinflammatory lipoxin A4, production and suppression of the proinflammatory hepoxilin A3, and leukotriene B4. Unearthing complex PAO1 pathogenic/virulence mechanisms, including effects on the host anti/proinflammatory responses, lipid metabolism, and ferroptotic cell death, points toward potentially new therapeutic and radiomitigative targets.

A new thiol-independent mechanism of epithelial host defense against Pseudomonas aeruginosa: iNOS/NO• sabotage of theft-ferroptosis.

Ferroptosis is a redox-driven type of regulated cell death program arising from maladaptation of three metabolic pathways: glutathione homeostasis, iron handling and lipid peroxidation. Though GSH/Gpx4 is the predominant system detoxifying phospholipid hydroperoxides (PLOOH) in mammalian cells, recently Gpx4-independent regulators of ferroptosis like ferroptosis suppressor protein 1 (FSP1) in resistant cancer lines and iNOS/NO• in M1 macrophages have been discovered. We previously reported that Pseudomonas aeruginosa (PA) utilizes its 15- lipoxygenase (pLoxA) to trigger ferroptotic death in epithelial cells by oxidizing the host arachidonoyl-phosphatidylethanolamine (ETE-PE) into pro-ferroptotic 15-hydroperoxy- arachidonyl-PE (15-HpETE-PE). Here we demonstrate that PA degrades the host GPx4 defense by activating the lysosomal chaperone-mediated autophagy (CMA). In response, the host stimulates the iNOS/NO•-driven anti-ferroptotic mechanism to stymie lipid peroxidation and protect GPx4/GSH-deficient cells. By using a co-culture model system, we showed that macrophage-produced NO• can distantly prevent PA stimulated ferroptosis in epithelial cells as an inter-cellular mechanism. We further established that suppression of ferroptosis in epithelial cells by NO• is enabled through the suppression of phospholipid peroxidation, particularly the production of pro-ferroptotic 15-HpETE-PE signals. Pharmacological targeting of iNOS (NO• generation) attenuated its anti-ferroptotic function. In conclusion, our findings define a new inter-cellular ferroptosis suppression mechanism which may represent a new strategy of the host against P. aeruginosa induced theft-ferroptosis.

PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells.

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.

Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death.

Ferroptotic death is the penalty for losing control over three processes-iron metabolism, lipid peroxidation and thiol regulation-that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NO•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells, whereas NO• donors empower resistance of M2 cells to ferroptosis. In vivo, M1 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (ETE)-PE intermediates and oxidatively truncated species by NO• donors and/or suppression of NO• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.

Partially Covered Versus Uncovered Self-Expandable Metal Stents: Coating Nor Diameter Affect Clinical Outcomes.

INTRODUCTION: Jaundice is a common initial presentation of malignant biliary stricture. In patients with life expectancies that are greater than 3 months, self-expanding metal stents (SEMS) offer a larger diameter stent with longer patency and fewer complications compared to plastic stents. There have been conflicting results in the published literature as to efficacy and safety between the various SEMS types and diameters. We compared stent coating (PCSEMS vs USEMS) and diameter on clinical outcomes regarding management of malignant biliary obstruction. METHODS: A retrospective cohort study was conducted using a database of consecutive patients who underwent an ERCP with biliary SEMS placement (only 8 and 10 mm) between 2009 and 2017. RESULTS: In total, 278 patients who had SEMS at ERCP for malignant biliary obstruction were included (213 PCSEMS vs 65 USEMS). The groups were demographically evenly matched. Clinical success rates and patency duration were not statistically significant between PCSEMS and USEMS (98.1% vs 95.5%, P = 0.36, and 302.5 vs 225.5 days, P = 0.72, respectively). Adverse event rates were similar between both PCSEMS and USEMS with regard to overall adverse events. Stent diameter did not have an impact on overall clinical success (98.9% vs 95.3%, P = 0.11) or patency duration (239 days vs 336 days, P = 0.51). CONCLUSIONS: Our comparison of PCSEMS versus USEMS and 8 mm versus 10 mm showed no difference in clinical efficacy or adverse events between the two SEMS coatings and diameter, illustrating that coating and size do not matter in regard to stent choice, despite prior suggestive data.

Updates in the management of intradural spinal cord tumors: a radiation oncology focus.

Primary spinal cord tumors represent a hetereogeneous group of central nervous system malignancies whose management is complex given the relatively uncommon nature of the disease and variety of tumor subtypes, functional neurologic deficits from the tumor, and potential morbidities associated with definitive treatment. Advances in neuroimaging; integration of diagnostic, prognostic, and predictive molecular testing into tumor classification; and developments in neurosurgical techniques have refined the current role of radiotherapy in the multimodal management of patients with primary spinal cord tumors, and corroborated the need for prospective, multidisciplinary discussion and treatment decision making. Radiotherapeutic technological advances have dramatically improved the entire continuum from treatment planning to treatment delivery, and the development of stereotactic radiosurgery and proton radiotherapy provides new radiotherapy options for patients treated in the definitive, adjuvant, or salvage setting. The objective of this comprehensive review is to provide a contemporary overview of the management of primary intradural spinal cord tumors, with a focus on radiotherapy.

Effectiveness and components of self-management interventions in adult cancer survivors: a protocol for a systematic review and planned meta-analysis.

BACKGROUND: Self-management interventions have been proposed as effective strategies to improve health and well-being and promote optimal coping in cancer survivors. Several reviews have shown benefits of self-management interventions on a variety of patient-reported outcomes. Effective self-management strategies in other chronic disease populations are typically based on theories of behavior change, but the extent of theoretical underpinnings in cancer self-management programs has not been evaluated to date. Our aim is to expand on previous reviews by evaluating the effectiveness of self-management interventions in cancer survivors as well as the theoretical components of such interventions. METHODS: We will conduct a systematic review of self-management interventions for adults who have completed primary treatment for their solid or hematological cancer. Interventions tested using experimental or quasi-experimental methods, with any type of comparator, will be included. A search strategy will be designed with a health sciences librarian and then performed using MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus, the Cochrane database of systematic reviews, the National Institutes of Health clinical trials registry, and the Cochrane CENTRAL registry of controlled trials. Data synthesis will include a narrative and tabular summary of the results. Appropriate statistical analysis may include a meta-analysis using random effects methods to determine the effectiveness of self-management interventions and a meta-regression to evaluate how characteristics of the interventions are associated with the intervention effect. Risk of bias will be evaluated using the Cochrane risk of bias tool or the Risk of Bias in Non-randomized studies tool (RoBANS). DISCUSSION: The results of this systematic review will add to previous reviews and expand the existing knowledge base of the effectiveness and active components of self-management interventions for adult cancer survivors. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018085300.

Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium.

Ferroptosis is a death program executed via selective oxidation of arachidonic acid-phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa-associated diseases such as CF and persistent lower respiratory tract infections.

Sex Disparities in Outcomes of Early Stage Colorectal Cancer: A Population-Based Study.

BACKGROUND: Women have been shown to experience longer overall survival after colorectal cancer (CRC) diagnosis than men even after adjusting for disease stage and management. However, the etiology of this observation is not well understood, and the impact of non-CRC health conditions on survival has not been described. We aimed to evaluate the prognostic role of sex on CRC-specific outcomes. PATIENTS AND METHODS: All patients who underwent primary resection of stage I to III CRC from 2001 to 2005, and who were referred to cancer centers in a large, representative Canadian province were reviewed. Baseline patient characteristics, including common comorbidities, were compared between men and women. Multivariable analysis was used to evaluate the associations between sex and survival outcomes. RESULTS: We identified 1837 patients. Median age was 69 (interquartile range 60-76) years, and there were 867 women (47%) and 970 men (53%). Men were more likely to report ischemic heart disease, diabetes, dyslipidemia, and obesity (all P < .001). On multivariable analysis, men had worse overall and recurrence-free survival compared to women (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.15-1.64; and HR = 1.40, 95% CI, 1.18-1.67, respectively). However, CRC-specific outcomes, including CRC-specific survival and time to recurrence, did not differ significantly between men and women (HR = 1.15, 95% CI, 0.91-1.45; and HR = 1.12, 95% CI, 0.90-1.40, respectively). CONCLUSION: Women diagnosed with early stage CRC lived longer and had better general health than men. When noncancer causes of death were excluded, however, the trajectory of CRC appeared similar irrespective of sex. Early identification and better management of comorbidities may narrow the survival gap between men and women.

Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database.

Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival in sorafenib-treated patients with HCC. Etiology of liver disease should be considered in future models and clinical trial designs.

Primary Care Versus Oncology-Based Surveillance Following Adjuvant Chemotherapy in Resected Pancreatic Cancer.

INTRODUCTION: High level evidence to guide surveillance following curative intent treatment for pancreatic cancer is lacking and this has likely resulted in wide variations in practice. We aim to describe patterns of surveillance and evaluate their impact on outcomes. METHODS: A total of 147 adult patients who received at least one cycle of adjuvant gemcitabine or 5-fluorouracil-based chemotherapy at any one of five British Columbia Cancer Agency centers between 2001 and 2015 were included. Surveillance strategies were classified into two categories: discharged to primary care physicians (PCPs) or follow-up at cancer centers (CC) that included regular clinical assessments, laboratory testing, and/or diagnostic imaging. RESULTS: Median age at diagnosis was 64 (range 38-85) years and 48% were men. More patients were followed by CC than by PCPs (66 vs. 44%). Among the measured prognostic factors, only patients with advanced tumor stage (T3/4) were more likely to be followed by cancer specialists (78 vs. 62%, P = 0.03), while other patient and disease characteristics were balanced between the two groups. In the entire cohort, 100 (68%) patients had a documented recurrence. Patients followed by CC were more likely to receive palliative chemotherapy at recurrence than those followed by PCPs (58 vs. 34%, respectively, P = 0.03). The median overall survival (OS) was 2.82 (95% CI 2.17-3.32) years in the CC group and 3.35 (95% CI 2.85-5.06) years in the PCP group while the median relapse-free survival (RFS) was 1.4 (95% CI 1.37-1.77) and 2.4 (95% CI 2.07-4.59) years, respectively. On multivariate analysis, there was no significant difference in OS between CC and PCP-based surveillance (HR 1.23; 95% CI 0.74-2.04, P = 0.40); however, RFS favored the PCP group (HR 1.62; 95% CI 1.01-2.56, P = 0.04, for the CC group). CONCLUSION: In this population-based analysis, surveillance tests and imaging performed by CC detected recurrences earlier when compared to follow-up by PCPs, but this did not result in OS differences. Patients with more advanced tumors were more likely to be seen at CC. PCPs may play a larger role in the follow-up care of selected low risk patients with resected pancreatic cancer.

Nanoemitters and innate immunity: the role of surfactants and bio-coronas in myeloperoxidase-catalyzed oxidation of pristine single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWCNTs) are experimentally utilized in in vivo imaging and photothermal cancer therapy owing to their unique physicochemical and electronic properties. For these applications, pristine carbon nanotubes are often modified by polymer surfactant coatings to improve their biocompatibility, adding more complexity to their recognition and biodegradation by immuno-competent cells. Here, we investigate the oxidative degradation of SWCNTs catalyzed by neutrophil myeloperoxidase (MPO) using bandgap near-infrared (NIR) photoluminescence and Raman spectroscopy. Our results show diameter-dependence at the initial stages of the oxidative degradation of sodium cholate-, DNA-, and albumin-coated SWCNTs, but not phosphatidylserine-coated SWCNTs. Moreover, sodium deoxycholate- and phospholipid-polyethylene glycol coated SWCNTs were not oxidized under the same reaction conditions, indicating that a surfactant can greatly impact the biodegradability of a nanomaterial. Our data also revealed that possible binding between MPO and surfactant coated-SWCNTs was unfavorable, suggesting that oxidation is likely caused by a hypochlorite generated through halogenation cycles of free MPO, and not MPO bound to the surface of SWCNTs. The identification of SWCNT diameters and coatings that retain NIR fluorescence during the interactions with the components of an innate immune system is important for their applications in in vivo imaging.

Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O.

The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmic sequestration. This activity is counteracted by BAP1 autodeubiquitination through intramolecular interactions. Significantly, we identified cancer-derived BAP1 mutations that abrogate autodeubiquitination and promote its cytoplasmic retention, indicating that BAP1 autodeubiquitination ensures tumor suppression. The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1. Finally, we established a putative targeting consensus sequence of UBE2O and identified numerous chromatin remodeling factors as potential targets, several of which tested positive for UBE2O-mediated ubiquitination. Thus, UBE2O defines an atypical ubiquitin-signaling pathway that coordinates the function of BAP1 and establishes a paradigm for regulation of nuclear trafficking of chromatin-associated proteins.

Arginase and C-reactive protein as potential serum-based biomarker of head and neck squamous cell carcinoma patients of north east India.

Head and neck squamous cell carcinoma (HNSCC) diagnosis involves histopathological investigations with intervention procedures. Widely accepted biochemical panels for HNSCC detection is not available yet. We tried to find out the effectiveness of the serum-based biochemical markers for their prognostic significance in HNSCC. We collected fresh blood samples of 80 HNSCC patients and 100 healthy subjects. Samples were analyzed for absolute levels of arginase (ARG), ornithine aminotransferase (OAT), catalase (CAT), lactate dehydrogenase (LDH), amylase (AMY) activity, and C-reactive protein (CRP). Receiver-operator characteristic curves and Fagan's nomograms were generated. Out of six parameters studied, four (OAT, CAT, LDH, and AMY) did not show biologically significant differences to be used as biomarkers. Significant elevation in serum ARG and CRP levels were observed in HNSCC. The individual estimation of ARG and CRP showed lower specificity, but their combination improved the specificity level to 95%. Our results suggest that serum ARG and CRP together can efficiently diagnose HNSCC.

Efficacy of the non-adenosine analogue A1 adenosine receptor agonist (BR-4935) on cardiovascular function after cardiopulmonary bypass.

BACKGROUND: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. RESULTS: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. CONCLUSION: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.