Impact of Treatment Modality on Quality of Life Among Uterine Cancer Survivors.

AIMS: Our understanding of the impact of adjuvant therapy on longitudinal quality of life (QoL) following surgery for patients with uterine cancer is limited. The purpose of this study was to compare QoL in patients who have undergone surgery with or without radiation therapy for uterine cancer. MATERIALS AND METHODS: This was a cross-sectional cohort study that examined women treated for uterine cancer at MD Anderson Cancer Center from 2006 to 2017. Participants included those who underwent hysterectomy/bilateral salphingo-oophorectomy alone, with brachytherapy or external beam radiation therapy (EBRT). A non-cancer cohort of women who underwent a hysterectomy/bilateral salphingo-oophorectomy for benign indications was also identified (non-CA). To compare QoL we used the Functional Assessment of Cancer Therapy - Endometrial survey (FACT-En), a validated survey used to assess QoL. The survey has five subscales: physical, social, emotional, functional and an endometrial cancer-specific subscale. Cohorts were compared using ANOVA tests. RESULTS: In total, 309 women responded to the questionnaire (hysterectomy/bilateral salphingo-oophorectomy 64, brachytherapy 77, EBRT 96, non-CA 72). The median time from surgery to survey completion was 6.7 years. The mean total FACT-En score for the entire cohort was 144 [standard deviation 22]. Overall QoL was different between cohorts, with the EBRT cohort reporting the lowest QoL (mean 139.4 [21.6]) and the brachytherapy cohort the highest (150.6 [18.2], P = 0.006). Among patients who had undergone cancer treatment, the EBRT cohort reported the worst endometrial-specific QoL (53.5 [8.6]), while again the brachytherapy group reported the highest score (57.5 [6.1], P = 0.007). CONCLUSIONS: QoL differences in women who have undergone different treatments for uterine cancer may persist years after treatment. In women with endometrial cancer who require adjuvant therapy, brachytherapy does not appear to have any long-term detriments on QoL.

Jak3 deficiency blocks innate lymphoid cell development.

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.

Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.

This corrects the article DOI: 10.1038/onc.2015.296.

[Distributions and associations between duration of sleep, daytime naps and insomnia symptoms among Chinese adults].

Objective: To investigate the distribution of sleep duration, daytime naps habits, and insomnia-related symptoms among participants from the China Kadoorie Biobank (CKB) study, and to examine the associations between the sleep-associated factors. Methods: A self-designed computer-based questionnaire was adopted to collect social-demographic information and lifestyle-related factors of the participants. A total of 452 829 Chinese adults aged 30-79 years, without self-reported histories of coronary heart disease, stroke, chronic obstructive pulmonary diseases or cancer, were included in this study. General linear regression and multinomial logistic regression models were used to estimate the distributions on duration of sleep, daytime naps habits, and insomnia-related symptoms in different populations, after adjusted for gender, age, and residential regions. Gender-specific logistic regression model was adopted to examine the associations between the above mentioned sleep-related factors. Results: The average sleep duration of the participants was 7.41 hours per day, with 20.3% of them having daytime naps all year round, but 40.1% only had daytime naps in summer, and 39.6% had no habits of daytime naps. 11.0%, 10.0%, and 2.1% of the participants reported having had symptoms as difficulty in falling asleep, waking up too early or with daytime dysfunction, respectively. There were significant differences on the distributions in sleep-related factors between participants with different gender, age, residential areas, education levels,household income, and marital status (P<0.05). Results from the logistic regression showed that longer sleep duration was associated with lower risks of insomnia-related symptoms trend (P<0.001). Factor as without habits of daytime naps seemed to be associated with higher risks of insomnia-related symptoms (P<0.05). Participants with longer sleep duration were more likely to have the habit of taking daytime naps (P<0.05). Conclusions: The distributions of sleep duration, habits on daytime naps and insomnia-related symptoms varied according to the differences on social-demographic factors. There were associations existed between the sleeping-related factors, which would influence the promotion on optimal sleep duration and better quality of sleep.

Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.

This corrects the article DOI: 10.1038/onc.2015.296.

[Present situation and analysis of murine allergic rhinitis model].

There have been 20 years of history in the study of allergic rhinitis(AR) using a mice model. At present, the AR mice model still exists some problems in the selection of mice strains, allergens and adjuvant types, molding cycle, allergen dose, model judgment, and so on, which affects the authenticity and comparability of the research results. By gradually solving the problems existing in the mice AR model, it is of great significance to realize the standardization of AR model, and the depth of the AR research.

Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.

ZNF322A encoding a classical Cys2His2 zinc finger transcription factor was previously revealed as a potential oncogene in lung cancer patients. However, the oncogenic role of ZNF322A and its underlying mechanism in lung tumorigenesis remain elusive. Here we show ZNF322A protein overexpression in 123 Asian and 74 Caucasian lung cancer patients. Multivariate Cox regression analysis indicated that ZNF322A was an independent risk factor for a poor outcome in lung cancer, corroborating the Kaplan-Meier results that patients with ZNF322A protein overexpression had significantly poorer overall survival than other patients. Overexpression of ZNF322A promoted cell proliferation and soft agar growth by prolonging cell cycle in S phase in multiple lung cell lines, including the immortalized lung cell BEAS-2B. In addition, ZNF322A overexpression enhanced cell migration and invasion, whereas knockdown of ZNF322A reduced cell growth, invasion and metastasis abilities in vitro and in vivo. Quantitative proteomic analysis revealed potential ZNF322A-regulated downstream targets, including alpha-adducin (ADD1), cyclin D1 (CCND1), and p53. Using luciferase promoter activity assay combined with site-directed mutagenesis and sequential chromatin immunoprecipitation-PCR assay, we found that ZNF322A could form a complex with c-Jun and cooperatively activate ADD1 and CCND1 but repress p53 gene transcription by recruiting differential chromatin modifiers, such as histone deacetylase 3, in an AP-1 element dependent manner. Reconstitution experiments indicated that CCND1 and p53 were important to ZNF322A-mediated promotion of cell proliferation, whereas ADD1 was necessary for ZNF322A-mediated cell migration and invasion. Our results provide compelling evidence that ZNF322A overexpression transcriptionally dysregulates genes involved in cell growth and motility therefore contributes to lung tumorigenesis and poor prognosis.

[Effect of specific immunotherapy on the psychological health level and quality of life in patients with allergic rhinitis].

Objective: To study the effect of specific immunotherapy on the psychological health level and quality of life in patients with allergic rhinitis(AR).Method:Selected 97 cases diagnosed as moderate to severe persistent AR patients, were treated with specific immunotherapy for one year. All patients received the evaluation with symptom check list 90(SCL-90) and rhinoconjunctivitis quality of life questionnaire(RQLQ) before specific immunotherapy, six, and 12 months after specific immunotherapy.Result:The total scores, scores of somatization, obsessive, anxiety, depression and phobia in SCL-90 of AR patients after 12 months treatment were significantly lower than that before treatment（P < 0.05）. Total score of quality of life and subitem score in RQLQ of AR patients after 12 months treatment were obviously lower than that before treatment (P < 0.05）.Conclusion:Specific immunotherapy can effectively alleviate the clinical symptoms and improve psychological health level and quality of life of AR patients.

Self-reported myopia in Taiwan: 2005 Taiwan National Health Interview Survey.

PURPOSE: To determine the prevalence of self-reported myopia nationwide in Taiwan and its association with degrees of urbanization and education levels. METHODS: Data were obtained from the 2005 Taiwan National Health Interview Survey, a nationwide survey using multistage stratified systematic sampling. The presence of myopia, current residential areas, and education levels were ascertained by a structured questionnaire in participants ≥ 12 years of age. RESULTS: A total of 20,609 eligible persons were included in this study. The overall weighted prevalence of myopia in Taiwan was 46.7% (95% confidence interval: 45.9, 47.5%). The prevalence of myopia for persons aged 12-19, 20-39, 40-64, and ≥ 65 years was 70.3%, 65.4%, 30.4%, and 5.6%, respectively. Women had significantly higher rates of myopia than men for persons younger than 40 years of age (P<0.001). Myopia was significantly associated with both higher degrees of urbanization of current residential areas and higher education levels (both P<0.001). In young adult and adult groups, the effect of education levels on myopia was stronger than that of degrees of urbanization. CONCLUSION: The study provides a nation-wide prevalence data on myopia in Taiwan. Both degrees of urbanization and education levels are risk factors for myopia.

The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK.

MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

Mutations in the ATP2C1 gene in Chinese patients with Hailey-Hailey disease.

Hailey-Hailey disease (HHD; MIM 16960) is a rare autosomal dominant hereditary disorder characterized by recurrent eruption of vesicles and bullae, predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1). When we studied Chinese patients with HHD, we found two different heterozygous mutations, Q506X and G353V, the former previously reported in a Hungarian patient, and the latter being a novel mutation. In a 38-year-old patient from a four-generation pedigree with a 3-year history of severe recurrent blisters, we identified a C-->T transition at nucleotide 1696, c(1696C-->T), in exon 17 of ATP2C1, resulting in a nonsenes mutation, Gln506X, which resulted in a premature termination codon. In the second patient, who represented a occurrence of sporadic Hailey-Hailey disease, a G-->T transversion of nucleotide, c(G1238T), in exon 13 of ATP2C1 was detected, which resulted in a Gly353-->Val amino acid substitution (G353V). Our molecular findings further demonstrate that the mutational events in the human ATP2C1 gene encoding the hSPCA1 pump play an important role in the pathogenesis of HHD.

Primary placement of a titanium sleeve in hydroxyapatite orbital implants.

BACKGROUND: To study a new surgical option of primary placement of a titanium sleeve into hydroxyapatite implants during enucleation or evisceration. METHODS: A standard enucleation or cornea preserved evisceration was performed, followed by preplacement of a titanium sleeve into the hydroxyapatite implant by a hand drill sleeve driver. Care must be taken to ensure that the titanium sleeve is positioned centrally when the implant is put inside the orbital socket or eviscerated shell. The Tenon capsule and conjunctiva were meticulously closed with minimal tension. Complications such as sleeve exposure, coralline exposure, and infection of the titanium sleeve were closely observed. RESULTS: In all, 30 patients were treated in the above fashion with 10 enucleation and 20 evisceration procedures. The follow-up period ranged from 9 to 24 months. Three of the sleeves were found to have exposed spontaneously at 5 and 7 weeks following original surgery. They had no further complication except one sleeve loosening. The remaining 27 sleeves that did not spontaneously expose pursued secondary exposure of the titanium sleeve and peg insertion by conjunctival cutdown procedure 3 months after original surgery. Two sleeves were found to be oblique positioned after the conjunctival cutdown procedure. Fortunately, all the 30 patients were successfully fit with a peg-coupled prosthesis with good motility. CONCLUSION: Primary placement of a titanium sleeve into hydroxyapatite implants has several advantages, including high patient acceptance, technical simplicity, and office-based conjunctival cutdown pegging procedure. By avoiding the expense of postoperative imaging study and additional prosthetic modification, a more rapid and efficient rehabilitation is possible.

Surgical coverage of exposed hydroxyapatite implant with retroauricular myoperiosteal graft.

BACKGROUND: With the increasing use of hydroxyapatite orbital implants, the complication of exposure has become apparent to oculoplastic surgeons. Many kinds of patch grafts, such as sclera, dermis, and hard palate mucosa, have been used to cover exposed hydroxyapatite implants with inconsistent results. In this study, the authors use a newly developed technique, autogenous retroauricular myoperiosteal graft, and the results are reported. METHODS: A piece of retroauricular muscle together with its underlying periosteum was carefully harvested. This myoperiosteal graft was patched to the debrided hydroxyapatite exposure area with the periosteal surface facing outward. The margin of periosteal surface was secured with conjunctiva and left uncovered for the surrounding conjunctiva to epithelialise. RESULTS: Nine eyes with hydroxyapatite exposure more than 3 mm were managed with autogenous retroauricular myoperiosteal grafts. Seven cases were successfully treated with single graft surgery. The other two cases needed an additional graft surgery, and there was no re-exposure noted thereafter. Five patients received a successful insertion of the motility peg. All nine patients have been fitted with prosthesis with reasonable motility. There were no complication noted during more than 1 year of follow up. CONCLUSION: The thick composite nature of the myoperiosteal graft provides a durable and vascularised coverage for exposed hydroxyapatite implants. This technique offers an encouraging alternative for the management of exposed hydroxyapatite implants.

Valgancyclovir as maintenance therapy for cytomegalovirus retinitis in a lung transplant patient--a case report.

UNLABELLED: The purpose of this article is to report the use of valgancyclovir as maintenance therapy for cytomegalovirus (CMV) retinitis in a lung transplanted patient. RESULT: A 30-year-old woman with underlying pulmonary lymphangioleiomyomatosis received a lung transplant 1 year ago. CMV retinitis developed 4 months later but subsided after intravenous ganciclovir treatment. Unfortunately, the CMV retinitis recurred three times in 1 year while on oral ganciclovir maintenance therapy. To treat the latest relapse, valgancyclovir 900 mg once daily was used as maintenance therapy after intravenous gancyclovir induction. With a 6-month follow-up, the fundoscopic examination revealed old atrophic scar and no active CMV retinits. The patient was able to maintain best-corrected visual acuity of 20/20 in both eyes. In conclusion, Valganciclovir may be used as maintenance therapy in CMV retinitis.

Enhanced proliferation and increased IFN-gamma production in T cells by signal transduced through TNF-related apoptosis-inducing ligand.

TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel member of TNF superfamily, induces apoptosis in transformed cell lines of diverse origin. TRAIL is expressed in most of the cells, and the expression is up-regulated in activated T cells. Four receptors for TRAIL have been identified, and there is complex interplay between TRAIL and TRAIL receptors in vivo. The actual biological function of TRAIL/TRAIL receptor is still not clear. Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. Cross-linking of TRAIL by plate-bound rTRAIL receptor, death receptor 4-Fc fusion protein enhanced T cell proliferation and increased IFN-gamma production in conjunction with immobilized suboptimal anti-CD3 stimulation in mouse splenocytes. The increase of T cell proliferation by death receptor 4-Fc was dose dependent, and this effect could be blocked by soluble rTRAIL proteins, indicating the occurrence of reverse signaling through TRAIL on T cell. The enhanced secretion of IFN-gamma mediated via TRAIL could be blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in inducing apoptosis by binding to the death receptors, TRAIL itself can enhance T cell proliferation after TCR engagement and signal the augmentation of IFN-gamma secretion via a p38-dependent pathway. This provides another example of reverse signaling by a member of TNF superfamily. In conclusion, our data suggest that TRAIL can itself transduce a reverse signal, and this may shed light on the biological function of TRAIL.

Solution structure of the tumor necrosis factor receptor-1 death domain.

Tumor necrosis factor receptor-1 death domain (TNFR-1 DD) is the intracellular functional domain responsible for the receptor signaling activities. The solution structure of the R347K mutant of TNFR-1 DD was solved by NMR spectroscopy. A total of 20 structures were calculated by means of hybrid distance geometry-simulated annealing using a total of 1167 distance constraints and 117 torsion angle constraints. The atomic rms distribution about the mean coordinate positions for the 20 structures for residues composing the secondary structure region is 0.40 A for the backbone atoms and 1.09 A for all atoms. The structure consists of six antiparallel alpha-helices arranged in a similar fashion to the other members of the death domain superfamily. The secondary structure and three-dimensional structure of R347K TNFR1-DD are very similar to the secondary structure and deduced topology of the R347A TNFR1-DD mutant. Mutagenesis studies identified critical residues located in alpha2 and part of alpha3 and alpha4 that are crucial for self-interaction and interaction with TRADD. Structural superposition with previously solved proteins in the death domain superfamily reveals that the major differences between the structures reside in alpha2, alpha3, and alpha4. Interestingly, these regions correspond to the binding sites of TNFR1-DD, providing a structural basis for the specificity of death domain interactions and its subsequent signaling event.