These results indicate dry eye's negative impact on everyday life, particularly in daily activities. Further research using disease-specific measures to examine dry eye's impact is underway.

The Cancer/Testis Antigens (CTAs) are a group of heterogeneous proteins that are typically expressed in the testis but aberrantly expressed in several types of cancer. Although overexpression of CTAs is frequently associated with advanced disease and poorer prognosis, the significance of this correlation is unclear since the functions of the CTAs in the disease process remain poorly understood. Here, employing a bioinformatics approach, we show that a majority of CTAs are intrinsically disordered proteins (IDPs). IDPs are proteins that, under physiological conditions in vitro, lack rigid 3D structures either along their entire length or in localized regions. Despite the lack of structure, most IDPs can transition from disorder to order upon binding to biological targets and often promote highly promiscuous interactions. IDPs play important roles in transcriptional regulation and signaling via regulatory protein networks and are often associated with dosage sensitivity. Consistent with these observations, we find that several CTAs can bind DNA, and their forced expression appears to increase cell growth implying a potential dosage-sensitive function. Furthermore, the CTAs appear to occupy ‘hub’ positions in protein regulatory networks that typically adopt a ‘scale-free’ power law distribution. Taken together, our data provide a novel perspective on the CTAs implicating them in processing and transducing information in altered physiological states in a dosage-sensitive manner. Identifying the CTAs that occupy hub positions in protein regulatory networks would allow a better understanding of their functions as well as the development of novel therapeutics to treat cancer.

ObjectiveTo develop and validate a comprehensive patient-reported outcomes instrument focusing on the impact of dry eye on everyday life (IDEEL).MethodsDevelopment and validation of the IDEEL occurred in four phases: 1) focus groups with 45 dry eye patients to develop a draft instrument, 2) item generation, 3) pilot study to assess content validity in 16 patients and 4) psychometric validation in 210 subjects: 130 with non-Sjögren's keratoconjunctivitis sicca, 32 with Sjögren's syndrome and 48 controls, and subsequent item reduction.ResultsFocus groups identified symptoms and the associated bother, the impact of dry eye on daily life and the patients' satisfaction with their treatment as the central concepts in patients' experience of dry eye. Qualitative analysis indicated that saturation was achieved for these concepts and yielded an initial 112-item draft instrument. Patients understood the questionnaire and found the items to be relevant indicating content validity. Patient input, item descriptive statistics and factor analysis identified 55 items that could be deleted. The final 57-item IDEEL assesses dry eye impact constituting 3 modules: dry eye symptom-bother, dry eye impact on daily life comprising impact on daily activities, emotional impact, impact on work, and dry eye treatment satisfaction comprising satisfaction with treatment effectiveness and treatment-related bother/inconvenience. The psychometric analysis results indicated that the IDEEL met the criteria for item discriminant validity, internal consistency reliability, test-retest reliability and floor/ceiling effects. As expected, the correlations between IDEEL and the Dry Eye Questionnaire (a habitual symptom questionnaire) were higher than between IDEEL and Short-Form-36 and EuroQoL-5D, indicating concurrent validity.ConclusionThe IDEEL is a reliable, valid and comprehensive questionnaire relevant to issues that are specific to dry eye patients, and meets current FDA patient-reported outcomes guidelines. The use of this questionnaire will provide assessment of the impact of dry eye on patient dry eye-related quality of life, impact of treatment on patient outcomes in clinical trials, and may aid in treatment effectiveness evaluation.

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Prostate-associated gene 4 (PAGE4) is a cancer/testis antigen that is typically restricted to the testicular germ cells but is aberrantly expressed in cancer. Furthermore, PAGE4 is developmentally regulated with dynamic expression patterns in the developing prostate and is also a stress-response protein that is upregulated in response to cellular stress. PAGE4 interacts with c-Jun, which is activated by the stress-response kinase JNK1, and plays an important role in the development and pathology of the prostate gland. Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51. We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation. In vitro single molecule FRET indicates phosphorylation results in compaction of (still) intrinsically disordered PAGE4. Interestingly, however, while our previous observations indicated that the wild-type nonphosphorylated PAGE4 protein interacted with c-Jun [RajagopalanK.RajagopalanK.24263171Biochim, Biophys. Acta20141842154], here we show that phosphorylation of PAGE4 weakens its interaction with c-Jun in vitro. These data suggest that phosphorylation induces conformational changes in natively disordered PAGE4 resulting in its decreased affinity for c-Jun to promote interaction of c-Jun with another, unidentified, partner. Alternatively, phosphorylated PAGE4 may induce transcription of a novel partner, which then potentiates c-Jun transactivation. Regardless, the present results clearly implicate PAGE4 as a component of the stress-response pathway and uncover a novel link between components of this pathway and prostatic development and disease.

BackgroundMultiple sclerosis (MS) is a chronic progressive neurological disease and the majority of patients will experience some degree of impaired mobility. We evaluated the prevalence, severity and burden of walking and mobility problems (WMPs) in 5 European countries.MethodsThis was a cross-sectional, patient record-based study involving 340 neurologists who completed detailed patient record forms (PRF) for patients (>18 years) attending their clinic with MS. Patients were also invited to complete a questionnaire (PSC). Information collected included demographics, disease characteristics, work productivity, quality of life (QoL; EuroQol-5D and Hamburg Quality of Life Questionnaire Multiple Sclerosis [HAQUAMS]) and mobility (subjective patient-reported and objectively measured using the timed 25 foot walk test [T25FW]). Relationships between WMPs and disease and other characteristics were examined using Chi square tests. Analysis of variance was used to examine relationships between mobility measures and work productivity.ResultsRecords were available for 3572 patients of whom 2171 also completed a PSC. WMPs were regarded as the most bothersome symptom by almost half of patients who responded (43%; 291/683). There was a clear, independent and strong directional relationship between severity of WMPs (subjective and objective) and healthcare resource utilisation. Patients with longer T25FW times (indicating greater walking impairment) were significantly more likely to require additional caregiver support (p < 0.0001), visit a variety of healthcare professionals including their primary care physicians (p = 0.0044) and require more long-term non-disease modifying drugs (p = 0.0001). A similar pattern was observed when subjective reporting of the severity of WMPs was considered. Work productivity was also markedly impacted by the presence of WMPs with fewer patients working full time and a reduction in weekly working hours as T25FW times and the subjective severity of WMPs increased.ConclusionsIn Europe, WMPs in MS represent a considerable personal and social burden both financially and in terms of quality of life. Interventions to improve mobility could have significant benefits for patients and society as a whole.

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