GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.

Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.

DLL3 regulates Notch signaling in small cell lung cancer.

Tumor heterogeneity plays a critical role in tumor development and response to treatment. In small-cell lung cancer (SCLC), intratumoral heterogeneity is driven in part by the Notch signaling pathway, which reprograms neuroendocrine cancer cells to a less/non-neuroendocrine state. Here we investigated the atypical Notch ligand DLL3 as a biomarker of the neuroendocrine state and a regulator of cell-cell interactions in SCLC. We first built a mathematical model to predict the impact of DLL3 expression on SCLC cell populations. We next tested this model using a single-chain variable fragment (scFv) to track DLL3 expression in vivo and a new mouse model of SCLC with inducible expression of DLL3 in SCLC tumors. We found that high levels of DLL3 promote the expansion of a SCLC cell population with lower expression levels of both neuroendocrine and non-neuroendocrine markers. This work may influence how DLL3-targeting therapies are used in SCLC patients.

Audiologic and Otologic Clinical Manifestations of Loeys-Dietz Syndrome: A Heritable Connective Tissue Disorder.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare genetic connective tissue disorder resulting from TGF-ß signaling pathway defects and characterized by a wide spectrum of aortic aneurysm, arterial tortuosity, and various extravascular abnormalities. This study describes the audiologic, otologic, and craniofacial manifestations of LDS. STUDY DESIGN: Consecutive cross-sectional study. SETTING: Tertiary medical research institute. METHODS: Audiologic and clinical evaluations were conducted among 36 patients (mean ± SD age, 24 ± 17 years; 54% female) with genetically confirmed LDS. Cases were categorized into genetically based LDS types 1 to 4 (TGFBR1, TGFBR2, SMAD3, TGFB2, respectively). Audiometric characteristics included degree and type of hearing loss: subclinical, conductive, mixed, and sensorineural. RESULTS: LDS types 1 to 4 included 11, 13, 5, and 7 patients, respectively. In LDS-1, 27% had bilateral conductive hearing loss; 9%, unilateral mixed; and 36%, subclinical. In LDS-2, 38% had conductive hearing loss and 38% subclinical. In LDS-3 and LDS-4, 40% and 43% had bilateral sensorineural hearing loss, respectively. Degree of hearing loss ranged from mild to moderate. Bifid uvula was observed only in LDS-1 (55%) and LDS-2 (62%). Submucosal/hard cleft palates were primarily in LDS-1 and LDS-2. Posttympanostomy tympanic membrane perforations occurred in 45% (10/22 ears) of LDS-1 and LDS-2. There were 4 cases of cholesteatoma: 3 middle ear (LDS-1 and LDS-2) and 1 external ear canal (LDS-3). CONCLUSION: Conductive hearing loss, bifid uvula/cleft palate, and posttympanostomy tympanic membrane perforation are more common in LDS-1 and LDS-2 than LDS-3 and LDS-4, while sensorineural hearing loss was present only in LDS-3 and LDS-4. These LDS-associated key clinical presentations may facilitate an early diagnosis of LDS and thus prompt intervention to prevent related detrimental outcomes.

Streamlining the Cochlear Implant Evaluation: Utility of Community Audiometry in Cochlear Implant Candidacy Assessment.

OBJECTIVE: To identify redundancy in the cochlear implant candidacy evaluation and assess its financial impact. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care academic cochlear implant center. PATIENTS: One hundred thirty-five patients referred for cochlear implant candidacy evaluation from 2004 through 2019. INTERVENTION: Community and academic audiometry were compared in a matched-pair analysis. MAIN OUTCOME MEASURES: Pure-tone audiometry and word recognition scores (WRS) were compared using the Wilcoxon signed-rank test. Cost of repeated audiometry was estimated using the Medicare Provider Utilization and Payment data. RESULTS: The majority of pure-tone thresholds (PTT) and pure-tone averages (PTA) had no statistically significant differences between community and academic centers. Only air PTT at 2000 Hz on the right and air PTA on the right demonstrated differences with α = 0.05 after Bonferroni correction. Despite statistical differences, mean differences in PTT and PTA were all under 3.5 dB. WRS were on average lower at the academic center, by 14.7% on the right (p < 0.001) and 10.6% on the left (p = 0.003). Repeating initial audiometry costs patients up to $60.58 and costs the healthcare system up to $42.94 per patient. CONCLUSIONS: Pure-tone audiometry between community and academic centers did not demonstrate clinically significant differences. Lower academic WRS implies that patients identified as potential cochlear implant candidates based on community WRS are likely suitable to proceed to sentence testing without repeating audiometry, saving patients and the healthcare system time and resources.

Activation and Monitoring of mtDNA Damage in Cancer Cells via the "Proton-Triggered" Decomposition of an Ultrathin Nanosheet.

Mitochondrial DNA (mtDNA) damage is a very important molecular event, which has significant effects on living organisms. Therefore, a particularly important challenge for biomaterials research is to develop functionalized nanoparticles that can activate and monitor mtDNA damage and instigate cancer cell apoptosis, and as such eliminate the negative effects on living organisms. Toward that goal, with this research, we have developed a hydroxyapatite ultrathin nanosheet (HAP-PDCns)-a high Ca2+ content biomaterial. HAP-PDCns undergoes proton-triggered decomposition after entering cancer cells via clathrin-mediated endocytosis, and then, it selectively concentrates in the charged mitochondrial membrane. This kind of proton-triggered decomposition phenomenon facilitates mtDNA damage by causing instantaneous local calcium overload in the mitochondria of cancer cells, and inhibits tumor growth. Importantly, at the same time, a real-time green-red-green fluorescence change occurs that correlates with the degree of mtDNA deterioration because of the changes in the highest occupied molecular orbital-lowest unoccupied molecular orbital energy gaps during this process. Significantly, the decomposition and the fluorescence changes cannot be triggered in normal cells. Thus, HAP-PDCns can selectively induce apoptosis and the death of a cancer cell by facilitating mtDNA damage, but does not affect normal cells. In addition, HAP-PDCns can simultaneously monitor the degree of mtDNA damage. We anticipate that this design strategy can be generalized to develop other functionalized biomaterials that can be used to instigate the positive effects of mtDNA damage on living organisms while eliminating any negative effects.

Effects of foot orthosis on ground reaction forces and perception during short sprints in flat-footed athletes.

Prefabricated foot orthosis (FO) is commonly worn for flat foot management. This study aimed to investigate the kinetic and perceptual effects of wearing prefabricated FO among flat-footed athletes during bouts of sprints. Twenty male sprint-based sports athletes who had flat foot bilaterally ran at three test speeds (5, 6, 7 m/s) under two conditions: prefabricated FO and sham FO. Ground reaction force (GRF) variables and subjective perceptions were recorded. Kinetic variability of GRF variables were computed to indicate step-to-step variance. Biomechanically, wearing prefabricated FOs increased vertical impact force (p =.005), loading rate (p =.001), and kinetic variability of peak propulsive force (p =.038) and loading rate (p =.019) during sprinting speeds across 5 to 7 m/s. Subjectively, prefabricated FO provided better arch support (p =.001) but resulted in reduced forefoot cushioning (p =.001), heel cushioning (p =.002), and overall comfort (p =.008).

Antigen processing and presentation in cancer immunotherapy.

BACKGROUND: Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches. METHODS: Original articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed. RESULTS: Natural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC50 of greater than 500 nM. CONCLUSIONS: Antigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.

Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand.

Interleukin-6 (IL-6) family cytokines signal through multimeric receptor complexes, providing unique opportunities to create novel ligand-based therapeutics. The cardiotrophin-like cytokine factor 1 (CLCF1) ligand has been shown to play a role in cancer, osteoporosis, and atherosclerosis. Once bound to ciliary neurotrophic factor receptor (CNTFR), CLCF1 mediates interactions to coreceptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). By increasing CNTFR-mediated binding to these coreceptors we generated a receptor superagonist which surpassed the potency of natural CNTFR ligands in neuronal signaling. Through additional mutations, we generated a receptor antagonist with increased binding to CNTFR but lack of binding to the coreceptors that inhibited tumor progression in murine xenograft models of nonsmall cell lung cancer. These studies further validate the CLCF1-CNTFR signaling axis as a therapeutic target and highlight an approach of engineering cytokine activity through a small number of mutations.

The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. SIGNIFICANCE: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.

Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.

Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.

Near-Infrared Optical Contrast of Skull Base Tumors During Endoscopic Endonasal Surgery.

BACKGROUND: Near-infrared (NIR) tumor contrast is achieved through the "second-window ICG" technique, which relies on passive accumulation of high doses of indocyanine green (ICG) in neoplasms via the enhanced permeability and retention effect. OBJECTIVE: To report early results and potential challenges associated with the application of second-window ICG technique in endonasal endoscopic, ventral skull-base surgery, and to determine potential predictors of NIR signal-to-background ratio (SBR) using endoscopic techniques. METHODS: Pituitary adenoma (n = 8), craniopharyngioma (n = 3), and chordoma (n = 4) patients received systemic infusions of ICG (5 mg/kg) approximately 24 h before surgery. Dual-channel endoscopy with visible light and NIR overlay were photodocumented and analyzed post hoc. RESULTS: All tumors (adenoma, craniopharyngioma, chordoma) demonstrated NIR positivity and fluoresced with an average SBR of 3.9 ± 0.8, 4.1 ± 1.7, and 2.1 ± 0.6, respectively. Contrast-enhanced T1 signal intensity proved to be the single best predictor of observed SBR (P = .0003). For pituitary adenomas, the sensitivity, specificity, positive predictive value, and negative predictive value of NIR-guided identification of tumor was 100%, 20%, 71%, and 100%, respectively. CONCLUSION: In this preliminary study of a small set of patients, we demonstrate that second-window ICG can provide NIR optical tumor contrast in 3 types of ventral skull-base tumors. Chordomas demonstrated the weakest NIR signal, suggesting limited utility in those patients. Both nonfunctional and functional pituitary adenomas appear to accumulate ICG, but utility for margin detection for the adenomas is limited by low specificity. Craniopharyngiomas with third ventricular extension appear to be a particularly promising target given the clean brain parenchyma background and strong SBR.

Adaptive Returns of Deficient Systemic Plasma Immunoglobulin G Levels as Rehabilitation Biomarker After Emergency Colectomy for Fulminant Ulcerative Colitis.

Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for ulcerative colitis (UC). Emergency colectomies are performed for fulminant colitis (ie, toxic megacolon, profuse bleeding, perforation, or sepsis). The RPC and IPAA involve manipulation of the proximal ileum, which may influence the essential physiological function of gut-associated lymphoid tissues. Circulating plasma immunoglobulin G (p-IgG) deficiency is observed in patients with fulminant UC. In addition, increased levels have been reported in colonic tissues of active UC compared with quiescent disease. We aimed to examine levels of p-IgG for clinical evaluation following emergency colectomies in patients with fulminant UC compared with patients with quiescent disease having elective RPC operations. In total 45 patients received an ileoanal pouch (IAP) due to UC. In all, 27 patients were men and 18 were women. The mean age was 34 years (range: 18-55). Because of fulminant UC, 26 patients had emergency subtotal colectomies with terminal ileostomy (TI). During second operation, the rectum was excised, and an IAP with diverting loop ileostomy (DLI) was performed. Nineteen patients had elective operations and had colectomies performed in conjunction with the pouch operation. Mucosectomy was performed in all groups. As a last procedure, the DLI was closed. Blood samples for immunoglobulin G (IgG) analyses were collected from each patient before the colectomy, after the colectomy with TI (before construction of the pouch), during the period with pouches (prior to DLI closure), and at 1, 2, and 3 years and at mean 13.7 years (range: 10-20) after DLI closure. Immunoglobulin G was determined by immunonephelometric assay technique. The statistics were analyzed by analysis of variance and linear regression. Preoperatively, p-IgG was significantly lower in the patients who had emergency operations compared with the group that had elective operations, 9.9 ± 3.0 vs 11.5 ± 3.3 g/L (P < .03). During the manipulative period with TI and/or DLI, the p-IgG levels were increased in both points, but the increase was not statistically significant (P = .26 and P = .19). During functional IAP at 1, 2, and 3 years and at mean 13.7 years (range: 10-20), there was a statistical increase in p-IgG levels (P < .002, P < .005, P < .005, and P < .0001) compared with preoperative levels. These changes did not correlate with episodes of pouchitis (P = .51). In patients having elective operations, p-IgG did not change preoperatively. After 12 months with functional pouches, the p-IgG levels were similar in both groups to the elective patient group preoperatively. In conclusion, p-IgG was found to be significantly lower in the emergency surgery patients compared with the elective surgery group preoperatively. This difference was probably due to increased losses and impaired gut lymphoid tissue production of IgG in the acute fulminant phase of UC. After 12 months of DLI closure, significant differences were no longer found between the emergency and elective surgery groups. Restoration and increased p-IgG levels after RPC would be due to an exaggerated response to make up for lower precolectomy values and may be interpreted as a rehabilitation biomarker.

Plasma cortisol as a noninvasive biomarker to assess severity and prognosis of patients with craniocerebral injury.

OBJECTIVE: The aim of this work is to evaluate the usefulness of plasma cortisol levels in determining the severity and prognosis in patients with a craniocerebral injury. PATIENTS AND METHODS: About 90 patients with craniocerebral injury and 40 control subjects were selected prospectively for the study. The plasma cortisol level was measured on 1st, 3rd, 7th and 21st day after admission into the hospital. The patients with craniocerebral injury were divided into two groups according to the Glasgow Coma Scale (GCS 3-5 and GCS 6-8), and within each group sub-groups namely Death and Survival were made based on survival status of patients. RESULTS: The plasma cortisol levels during the 1st and 3rd days were significantly increased in both GCS 3-5 and GCS 6-8 groups in comparison with control (p < 0.01); further, the GCS 3-5 group had higher plasma cortisol levels than GCS 6-8 (p < 0.05). The plasma cortisol level during the 1st and 3rd days in Death and Survival groups were significantly higher than the control (p < 0.05). Further, during the 7th day, plasma cortisol level was significantly elevated in the Death group than Survival group (p < 0.05). CONCLUSIONS: Since we found a significant association between plasma cortisol level and severity (Glasgow Coma Scale) and prognosis in patients with craniocerebral injury, the plasma cortisol level can be used as a non-invasive biomarker to assess the severity and prognosis in craniocerebral injury patients.

Anger expression, self-efficacy and interpersonal competency of Korean nursing students.

AIM: The purpose of this study was to determine whether self-efficacy mediated the relationship between anger expression and interpersonal competency in South Korean nursing students. BACKGROUND: Interpersonal competency allows nursing students to increase their self-confidence in caring for patients. There is evidence of complex relationships between anger expression, self-efficacy and interpersonal competency. Self-efficacy could be considered a potential mediator in the association between anger expression and interpersonal competency in nursing students. However, few studies have investigated the mediatory role of self-efficacy in this association. METHODS: A descriptive, cross-sectional study was conducted. In total, 207 Korean nursing students completed a structured questionnaire. Measurement tools included the State-Trait Anger Expression Inventory, Self-efficacy Scale and Interpersonal Competence Questionnaire. FINDINGS: Significant correlations were observed between anger expression, self-efficacy and interpersonal competency. Self-efficacy exerted a partial mediatory effect on the relationships between interpersonal competency and anger-in and anger-control within the anger expression subscales. CONCLUSION: The study demonstrated that appropriate anger expression could result in enhanced interpersonal competency via an increase in self-efficacy. IMPLICATIONS FOR NURSING AND HEALTH POLICY: The results concerning the mediatory role of self-efficacy in the association between anger expression and interpersonal competency have provided new knowledge for nursing educators, managers and researchers, allowing them to support nursing students' interpersonal competency. Nursing schools should be required to evaluate students' anger expression patterns and to increase self-efficacy when developing education programmes that provide interpersonal training for nursing students.

Factor affecting happiness among nursing students in South Korea.

WHAT IS KNOWN ON THE SUBJECT?: Despite the increased interest in nursing students' happiness in South Korea, few studies have attempted to identify factors influencing their happiness. Therefore, nursing educators should consistently investigate the factors influencing happiness and develop strategies to improve happiness among Korean nursing students. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study confirmed that there were positive correlations between grateful disposition, social support and happiness. In addition, grateful disposition and support from intimate people were identified as predictors of happiness in Korean nursing students. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Development of intervention programmes to help nursing students increase grateful disposition and support from intimate people may be helpful for improving happiness. These programmes can include activity, such as writing a gratitude journal, and extracurricular programmes, such as mentoring programmes between seniors and juniors and/or professor and student. ABSTRACT: Introduction Happiness is very important in the training and development of nursing students as future nurses. However, nursing students experience a high level of stress and low level of happiness in South Korea. Aim This study aimed to investigate factors that affect happiness among nursing students in South Korea. Method Data were collected from a total of 241 nursing enrolled in two 4-year baccalaureate nursing programmes in South Korea, using a self-administrated questionnaire. To identify predictors of happiness, stepwise regression analysis was conducted. Results The results indicated that grateful disposition and support from intimate people significantly predict happiness among Korean nursing students. These two factors accounted for 38.0% of the variance in happiness. Discussion This study indicated grateful disposition and support from intimate people as factors promoting happiness in nursing students. The findings highlight grateful disposition and support from intimate people as important factors when developing effective interventions that foster nursing students' happiness.

Long noncoding ribonucleic acids maternally expressed gene 3 inhibits lung cancer tumor progression through downregulation of MYC.

OBJECTIVE: Long noncoding ribonucleic acids (RNAs) nowadays emerge as important biomarkers or potential therapeutic targets discussed in human cancers. Among them, maternally expressed gene 3 (MEG3) is known to be decreased in a variety of malignancies. MATERIALS AND METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of MEG3 in forty pairs of lung cancer (LC) tissues. Overexpression of MEG3 was carried out, and we determined its effect on cell proliferation, apoptosis, and migration evaluated by cell counting kit-8, flow cytometric, and transwell analysis. Messenger RNA and protein expression of MYC were determined by qRT-PCR and western blot, respectively. RESULTS: The expression of MEG3 was downregulated in LC tissues. Forced expression of MEG3 led to reduced abilities of cell proliferation and elevated apoptosis rate. It also slightly inhibited cell migration capacity in vitro. In addition, MYC was inhibited by MEG3 overexpression at both transcriptional and translational levels. CONCLUSION: Our findings revealed MEG3 could regulate LC progression and serve as an important target for LC treatment.

A chemically cross-linked knottin dimer binds integrins with picomolar affinity and inhibits tumor cell migration and proliferation.

Molecules that target and inhibit αvß3, αvß5, and α5ß1 integrins have generated great interest because of the role of these receptors in mediating angiogenesis and metastasis. Attempts to increase the binding affinity and hence the efficacy of integrin inhibitors by dimerization have been marginally effective. In the present work, we achieved this goal by using oxime-based chemical conjugation to synthesize dimers of integrin-binding cystine knot (knottin) miniproteins with low-picomolar binding affinity to tumor cells. A non-natural amino acid containing an aminooxy side chain was introduced at different locations within a knottin monomer and reacted with dialdehyde-containing cross-linkers of different lengths to create knottin dimers with varying molecular topologies. Dimers cross-linked through an aminooxy functional group located near the middle of the protein exhibited higher apparent binding affinity to integrin-expressing tumor cells compared with dimers cross-linked through an aminooxy group near the C-terminus. In contrast, the cross-linker length had no effect on the integrin binding affinity. A chemical-based dimerization strategy was critical, as knottin dimers created through genetic fusion to a bivalent antibody domain exhibited only modest improvement (less than 5-fold) in tumor cell binding relative to the knottin monomer. The best oxime-conjugated knottin dimer achieved an unprecedented 150-fold increase in apparent binding affinity over the knottin monomer. Also, this dimer bound 3650-fold stronger and inhibited tumor cell migration and proliferation compared with cilengitide, an integrin-targeting peptidomimetic that performed poorly in recent clinical trials, suggesting promise for further therapeutic development.

The undervalued self: social class and self-evaluation.

Social class ranks people on the social ladder of society, and in this research we examine how perceptions of economic standing shape the way that individuals evaluate the self. Given that reminders of one's own subordinate status in society are an indicator of how society values the self in comparison to others, we predicted that chronic lower perceptions of economic standing vis-à-vis others would explain associations between objective social class and negative self-evaluation, whereas situation-specific reminders of low economic standing would elicit negative self-evaluations, particularly in those from lower-class backgrounds. In Study 1, perceptions of social class rank accounted for the positive relationship between objective material resource measures of social class and self-esteem. In Study 2, lower-class individuals who received a low (versus equal) share of economic resources in an economic game scenario reported more negative self-conscious emotions-a correlate of negative self-evaluation-relative to upper-class individuals. Discussion focused on the implications of this research for understanding class-based cultural models of the self, and for how social class shapes self-evaluations chronically.

Oxford unicompartmental knee arthroplasty versus age and gender matched total knee arthroplasty - functional outcome and survivorship analysis.

We compared the medium-term outcomes of age and gender matched patients with unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). We retrospectively reviewed the pain, function and total knee society scores (KSS) for 602 UKAs and age and gender matched TKAs between 2001 and 2013. Function scores remained significantly better in UKAs from preoperative until 3years follow up. The change of function scores was not significantly different. TKAs performed better than UKAs for pain scores. Total KSS for both groups were not significantly different in the study. Fewer medical complications were reported in UKA group. 6.30% of UKAs and 2.99% of TKAs were revised. The theoretical advantages of UKA were not borne out, other than in immediate postoperative complications.

Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi anemia cells.

Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Majority of the 15 FA genes and encoded proteins characterized so far are integrated into DNA repair pathways, however, other important functions cannot be excluded. FA cells are sensitive to oxidants, and accumulation of oxidized proteins has been characterized for several FA subgroups. Clinical phenotypes of both FA and other closely related diseases suggest altered functions of mitochondria, organelles responsible for cellular energetic metabolism, and also serving as an important producer and the most susceptible target from reactive oxidative species (ROS). In this study, we have shown that elevated level of mitochondrial ROS in FA cells is in parallel with the decrease of mitochondrial membrane potential, the decrease of ATP production, impaired oxygen uptake and pathological changes in the morphology of mitochondria. This is accompanied by inactivation of enzymes that are essential for the energy production (F1F0ATPase and cytochrome C oxidase) and detoxification of ROS (superoxide dismutase, SOD1). In turn, overexpression of SOD1 could rescue oxygen consumption rate in FA-deficient cells. Importantly, the depletion of mitochondria improved survival rate of mitomycin C treated FA cells suggesting that hypersensitivity of FA cells to chemotherapeutic drugs could be in part due to the mitochondria-mediated oxidative stress. On the basis of our results, we propose that deficiency in FA genes lead to disabling mitochondrial ROS-scavenging machinery further affecting mitochondrial functions and suppressing cell respiration.