The accuracy of simple, feasible alternatives to polysomnography for assessing sleep in intensive care: An observational study.

BACKGROUND: Sleep disturbance is common in intensive care patients. Understanding the accuracy of simple, feasible sleep measurement techniques is essential to informing their possible role in usual clinical care. OBJECTIVE: The aim of the study was to investigate whether sleep monitoring techniques such as actigraphy (ACTG), behavioural assessments, and patient surveys are comparable with polysomnography (PSG) in accurately reporting sleep quantity and quality among conscious, intensive care patients. METHODS: An observational study was conducted in 20 patients admitted to the intensive care unit (ICU) for a minimum duration of 24 h, who underwent concurrent sleep monitoring via PSG, ACTG, nursing-based observations, and self-reported assessment using the Richards-Campbell Sleep Questionnaire. RESULTS: The reported total sleep time (TST) for the 20 participants measured by PSG was 328.2 min (±106 min) compared with ACTG (362.4 min [±62.1 min]; mean difference = 34.22 min [±129 min]). Bland-Altman analysis indicated that PSG and ACTG demonstrated clinical agreement and did not perform differently across a number of sleep variables including TST, awakening, sleep-onset latency, and sleep efficiency. Nursing observations overestimated sleep duration compared to PSG TST (mean difference = 9.95 ± 136.3 min, p > 0.05), and patient-reported TST was underestimated compared to PSG TST (mean difference = -51.81 ± 144.1 7, p > 0.05). CONCLUSIONS: Amongst conscious patients treated in the ICU, sleep characteristics measured by ACTG were similar to those measured by PSG. ACTG may provide a clinically feasible and acceptable proxy approach to sleep monitoring in conscious ICU patients.

Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

BACKGROUND: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. PATIENTS AND METHODS: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. RESULTS: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). CONCLUSION: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

The feasibility and reliability of actigraphy to monitor sleep in intensive care patients: an observational study.

BACKGROUND: Sleep amongst intensive care patients is reduced and highly fragmented which may adversely impact on recovery. The current challenge for Intensive Care clinicians is identifying feasible and accurate assessments of sleep that can be widely implemented. The objective of this study was to investigate the feasibility and reliability of a minimally invasive sleep monitoring technique compared to the gold standard, polysomnography, for sleep monitoring. METHODS: Prospective observational study employing a within subject design in adult patients admitted to an Intensive Care Unit. Sleep monitoring was undertaken amongst minimally sedated patients via concurrent polysomnography and actigraphy monitoring over a 24-h duration to assess agreement between the two methods; total sleep time and wake time. RESULTS: We recruited 80 patients who were mechanically ventilated (24%) and non-ventilated (76%) within the intensive care unit. Sleep was found to be highly fragmented, composed of numerous sleep bouts and characterized by abnormal sleep architecture. Actigraphy was found to have a moderate level of overall agreement in identifying sleep and wake states with polysomnography (69.4%; K = 0.386, p < 0.05) in an epoch by epoch analysis, with a moderate level of sensitivity (65.5%) and specificity (76.1%). Monitoring accuracy via actigraphy was improved amongst non-ventilated patients (specificity 83.7%; sensitivity 56.7%). Actigraphy was found to have a moderate correlation with polysomnography reported total sleep time (r = 0.359, p < 0.05) and wakefulness (r = 0.371, p < 0.05). Bland-Altman plots indicated that sleep was underestimated by actigraphy, with wakeful states overestimated. CONCLUSIONS: Actigraphy was easy and safe to use, provided moderate level of agreement with polysomnography in distinguishing between sleep and wakeful states, and may be a reasonable alternative to measure sleep in intensive care patients. Clinical Trial Registration number ACTRN12615000945527 (Registered 9/9/2015).

Reduced rotavirus vaccine efficacy in protein malnourished human-faecal-microbiota-transplanted gnotobiotic pig model is in part attributed to the gut microbiota.

The low efficacy of human rotavirus (HRV) vaccines in low- and middle-income countries (LMIC) remains a major challenge for global health. Protein-calorie malnutrition (kwashiorkor) affects the gut microbiota and compromises immune development, leading to environmental enteropathy, vaccine failures, and increased susceptibility to enteric diseases in young children. Relationship between diet and reduced vaccine efficacy in developing countries is not well established; therefore, we investigated the interconnections between the host-microbiota-nutrition-HRV vaccine using HRV-vaccinated, human infant faecal microbiota (HIFM)-transplanted neonatal gnotobiotic pigs fed with a protein deficient or sufficient diet. The microbiota from faecal, intestinal (duodenum, ileum, jejunum, and colon), and systemic tissue (liver, spleen, and mesenteric lymph node [MLN]) samples was analysed before and after HRV challenge using MiSeq 16S rRNA sequencing. Overall, microbiota from deficient fed HIFM pigs displayed, compared to the sufficient group, significantly higher Shannon index, especially in the faeces and lower intestines; higher level of Proteus and Enterococcus, and lower level of Bifidobacterium, Clostridium, and Streptococcus in the three types of samples collected (P<0.05); and higher unique operational taxonomic units (OTUs), especially in the systemic tissues. Further, the multivariate analysis between microbiota and immunologic data showed that 38 OTUs at the genus level correlated (r2≤0.5 or ≥-0.5; P<0.05) with at least one host immune response parameter (regulatory [Tregs and transforming growth factor-ß], effectors [interferon (IFN)-γ+ CD4+ and CD8+ T cells, IFN-γ and interleukin (IL)-12], and inflammatory [tumour necrosis factor-α, IL-17 and IL-22]) and with opposite trends between diet groups. Differences described above were increased after HRV challenge. We demonstrated that a protein deficient diet affects the composition of the gut microbiota and those changes may further correlate with immune responses induced by HRV and perturbed by the deficient diet. Thus, our findings suggest that the reduced efficacy of HRV vaccine observed in Gn pig model is in part attributed to the altered microbiota composition.

A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

Gender difference in clinical and genetic characteristics of Brugada syndrome: SADS-TW BrS registry.

BACKGROUND: Brugada syndrome (BrS) is a heritable sudden cardiac death (SCD) disease with male predominance. Information on gender difference of BrS remains scarce. AIM: To investigate the gender difference of BrS in Han Chinese. DESIGN: We consecutively enrolled 169 BrS patients (153 males and 16 females) from Han Chinese in Taiwan from 1998 to 2017. METHODS: Clinical characteristics, electrocardiographic parameters and SCN5A mutation status were compared between genders. RESULTS: The percentage of family history of SCD in females was slightly higher (31.3% vs. 15%, P = 0.15). Females exhibited longer QTc (457.8 ± 33.0 vs. 429.5 ± 42.1 ms, P < 0.01). Regarding cumulative event occurrence by age, Mantel-Cox test showed females had earlier age of onset of first cardiac events (SCD or syncope) than males (P = 0.049), which was mainly attributed to syncope (P < 0.01). Males with SCD exhibited longer QRS duration (114.2 ± 26.8 vs. 104.8 ± 15.3 ms, P = 0.02) and QTc (442.5 ± 57.4 vs. 422.9 ± 28.8 ms, P = 0.02). Males with syncope exhibited longer PR interval (181.2 ± 33.7 vs. 165.7 ± 27.1 ms, P = 0.01), whereas females with SCD or syncope had a trend towards slower heart rates (69.1 ± 9.6 vs. 82.2 ± 16.3 bpm, P = 0.10) than female with no or mild symptoms. There was no difference in the percentage of SCN5A mutation between genders. CONCLUSION: Gender difference is present in BrS. Females have longer QTc and suffer from syncope earlier than males. Risk of SCD in males is associated with boarder QRS complex and longer QTc, whereas risk of syncope is associated with longer PR interval in males and slower heart rate in females.

[Clinical research about needle-tract assisted standard percutaneous nephrolithotomy for the treatment of complicated upper urinary tract calculi].

Objective: To investigate the safety and efficacy of needle-tract assisted standard percutaneous nephrolithotomy (PCNL) for the treatment of complicated upper urinary tract calculi. Methods: The clinical data of 1 562 patients with complicated upper urinary calculi who received standard PCNL from December 2013 to December 2017 at Department of Urology, the First Affiliated Hospital of Xiamen University were retrospectively analyzed. There were large residual stones in 256 patients through B-ultrasound exploration after standard PCNL, could't be detected with nephoscope in standard PCNL tracts. 16 F mini PCNL tract were established in 120 cases for treatment of residual stones, while needle-tract were established in order to guide nephroscope to find residual stones in 126 cases. Needle-tract were transferred to 16 F mini PCNL tract for treatment of residual stones in 10 patients if these residual stones could't be detected through needle-tract. Operation time, change of hemoglobin level after operation, incidence of postoperative complications, time of hospitalization and rate of stone clearance were measured in two groups. The statistical methods used included t test, Wilcoxon rank sum test, and χ2 test. Results: There were 1 to 3 mini tracts (M(QR): 1(1)) established in the mini tracts group and 1 to 7 needle-tracts (M(QR): 3(2)) established in the needle-tract group (Z=-10.57, P=0.000). Compared with mini tract group, the operation time ((62.0±18.0) minutes vs. (84.0±15.5) minutes, t=10.242, P=0.000), hospitalization time ((4.40±0.86) days vs. (5.20±0.81) days, t=7.570, P=0.049), hemoglobin dropped ((1.31±0.47) g/L vs. (2.74±0.63) g/L, t=20.12, P=0.000), and incidence of postoperative complications (7.9% (10/126) vs. 19.2% (23/120), χ2=6.674, P=0.01) of needle-tract group were lower, while postoperative stone clearance rate was higher (89.7% vs. 76.7%, χ2=7.497, P=0.006). No perioperative severe complications such as pleural injury, pneumatothorax, perforation of renal, trauma of abdominal organ occurred in two groups. Conclusion: Needle-tract assisted standard PCNL for the treatment of complicated upper urinary calculi can significantly improve stone clearance rate, reduce operation time, decrease risk of kidney and surrounding organs damage.

Effect of antibiotic, probiotic, and human rotavirus infection on colonisation dynamics of defined commensal microbiota in a gnotobiotic pig model.

We developed a gnotobiotic (Gn) pig model colonised with defined commensal microbiota (DMF) to provide a simplified and controlled system to study the interactions between intestinal commensals, antibiotics (ciprofloxacin, CIP), probiotics (Escherichia coli Nissle 1917, EcN) and virulent human rotavirus (VirHRV). The DMF included seven gut commensal species of porcine origin that mimic the predominant species in the infant gut. Gn piglets were divided into four groups: DMF control (non-treated), DMF+CIP (CIP treated), DMF+CIP+EcN (CIP/EcN treated), DMF+EcN (EcN treated) and inoculated orally with 105 cfu of each DMF strain. The pig gut was successfully colonised by all DMF species and established a simplified bacterial community by post-bacteria colonisation day (PBCD) 14/post-VirHRV challenge day (PCD) 0. Overall, Bifidobacterium adolescentis was commonly observed in faeces in all groups and time points. At PCD0, after six days of CIP treatment (DMF+CIP), we observed significantly decreased aerobic and anaerobic bacteria counts especially in jejunum (P<0.001), where no DMF species were detected in jejunum by T-RFLP. Following HRV challenge, 100% of pigs in DMF+CIP group developed diarrhoea with higher diarrhoea scores and duration as compared to all other groups. However, only 33% of pigs treated with EcN plus CIP developed diarrhoea. EcN treatment also enhanced the bacterial diversity and all seven DMF species were detected with a higher proportion of Bifidobacterium longum in jejunum in the DMF+CIP+EcN group on PBCD14/PCD0. Our results suggest that EcN increased the proportion of B. longum especially in jejunum and mitigated adverse impacts of antibiotic use during acute-infectious diarrhoea. The DMF model with a simplified gut commensal community can further our knowledge of how commensals and probiotics promote intestinal homeostasis and contribute to host health.

Fracture liaison services for osteoporosis in the Asia-Pacific region: current unmet needs and systematic literature review.

The analysis aimed to identify the treatment gaps in current fracture liaison services (FLS) and to provide recommendations for best practice establishment of future FLS across the Asia-Pacific region. The findings emphasize the unmet need for the implementation of new programs and provide recommendations for the refinement of existing ones. The study's objectives were to evaluate fracture liaison service (FLS) programs in the Asia-Pacific region and provide recommendations for establishment of future FLS programs. A systematic literature review (SLR) of Medline, PubMed, EMBASE, and Cochrane Library (2000-2017 inclusive) was performed using the following keywords: osteoporosis, fractures, liaison, and service. Inclusion criteria included the following: patients ≥ 50 years with osteoporosis-related fractures; randomized controlled trials or observational studies with control groups (prospective or retrospective), pre-post, cross-sectional and economic evaluation studies. Success of direct or indirect interventions was assessed based on patients' understanding of risk, bone mineral density assessment, calcium intake, osteoporosis treatment, re-fracture rates, adherence, and mortality, in addition to cost-effectiveness. Overall, 5663 unique citations were identified and the SLR identified 159 publications, reporting 37 studies in Asia-Pacific. These studies revealed the unmet need for public health education, adequate funding, and staff resourcing, along with greater cooperation between departments and physicians. These actions can help to overcome therapeutic inertia with sufficient follow-up to ensure adherence to recommendations and compliance with treatment. The findings also emphasize the importance of primary care physicians continuing to prescribe treatment and ensure service remains convenient. These findings highlight the limited evidence supporting FLS across the Asia-Pacific region, emphasizing the unmet need for new programs and/or refinement of existing ones to improve outcomes. With the continued increase in burden of fractures in Asia-Pacific, establishment of new FLS and assessment of existing services are warranted to determine the impact of FLS for healthcare professionals, patients, family/caregivers, and society.

[The surgical treatment of ovarian cancer metastasis between liver and diaphragm: a report of 83 cases].

Objective: To explore the safety and feasibility of associating diaphragm resection and liver-diaphragmatic metastasis lesions resection for patients with advanced ovarian cancer. Methods: Retrospectively analysis 83 cases(98 times) of advanced ovarian cancer with liver-diaphragmatic metastasis between January 2012 and December 2016 at Department of Liver Surgery, Peking Union Medical College Hospital.The patients were aged from 19 to 75 years.Surgical procedure included metastatic lesions resection(43 times) and stripping(55 times). Operation status, post-operative complications, pathology results and follow-up of the patients were analyzed. Results: Fifteen patients received twice surgical treatment and 68 patients received one time surgical treatment. Postoperative hemorrhage in chest and between liver and diaphragm was not occurred in all cases.Dyspnea and low oxygen saturation were occurred in two cases of stripping patients and 1 case of metastatic lesions resection patients.Results of CT examination indicated that there was medium to large amount of ascites in right chests.The symptoms were relieved after placing thoracic closed drainage.Other patients were recovered smoothly.All patients were diagnosed as ovarian cancer by pathological examination. Conclusion: Associating diaphragm resection is safe and feasible for liver-diaphragmatic metastasis lesions from ovarian cancer.

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.

[Visual impact of sub-tenon's anesthesia during surgery for retinal detachment].

Objective: To investigate the visual impact and influence factors of sub-Tenon's anesthesia in retinal detachment patients during pars plana vitrectomy (PPV) or combined phacoemulsification and PPV surgery. Methods: In this prospective case series study, 104 consecutive patients who underwent PPV or combined phacoemulsification and PPV under sub-Tenon's anesthesia between October 2012 and December 2013 were enrolled. Intraoperatively, the patients were asked whether they could see the light of the operating microscope or not at 5 minutes after sub-Tenon's anesthesia, and at the end of phacoemulsification, core vitreous removal, peripheral vitreous removal and the whole surgery, with their contralateral eyes being covered tightly and no photobleaching. The best corrected visual acuity and visual evoked potentials were examined and compared with each other preoperatively and at 1.5 months and 3 months postoperatively. Chi-square test was used to compare the detection rate of amaurosis between different modus operandi and whether covered contra-lateral eye. Student-t test was used to compare the difference of age and preoperative BCVA between the patients with or without experienced amaurois. Lastly, BCVA between different times were tested by one-way ANOVA analysis. Results: Without covering the contralateral eyes, the incidence of no light perception in various surgical steps was 0%, while it was 72.1%(75/104), 93.8%(75/80), 96.2%(100/104), 96.2%(100/104) and 86.5%(90/104) at the five timepoints, respectively, when the contralateral eyes were covered tightly. The incidence was 51.9%(54/104), 85.0%(68/80), 85. 6%(89/104), 84.6%(69/104) and 66.3%(88/104), respectively, after photobleaching was excluded. Approximately 95.2%(99/104) of patients reported no light perception at least once, 54.5%(54/99) reported no light perception 5 minutes after sub-Tenon's anesthesia, and 30.3%(30/99) recovered light perception when the surgery was finished. All eyes recovered to at least light perception on the first postoperative day. The best corrected visual acuity and visual evoked potentials at 1.5 months and 3 months postoperatively were significantly better than those before surgery. The BCVA was 1.75±0.78 preoperative, 0.96±0.63 1.5 months after operation, and 0.92±0.57 3 months after operation. There was a significant statistical difference between preoperative BCVA and postoperative BCVA (F=50.61, P<0.01) . In patients without waveform detection preoperatively, PVEP waveform could be found in 43.6% and 61.4% of the pactients at 1.5 months and 3 months after operation respectively. In those had certain waveform preoperatively, PVEP amplitudes rise significantly after surgery (t(1.5)=-2.69, t(3)=-2.97, P<0.05) . Conclusions: No light perception was detected in various surgical steps of vitrectomy under sub-Tenon's anesthesia in most patients. The blocking of optic nerve conduction may be caused by sub-Tenon' s anesthesia. Photobleaching can also have some effect. The incidence of no light perception during the surgery was not correlated with preoperative visual acuity, age and gender. Moreover, the effect was transient and harmless to visual function.(Chin J Ophthalmol, 2017, 53: 332-337).

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.

The upper-limb volumetric changes in breast cancer survivors with axillary web syndrome.

Whether upper-limb swelling is associated with axillary web syndrome (AWS) is unknown. We recruited unilateral breast cancer (BC) patients who were scheduled for surgical intervention and lymph node dissection. The pre-operative assessment and post-operative assessment 3-4 weeks after surgery evaluated the upper-limb circumferential measurements, segmental limb volume, pain scores, grasp, shoulder range of motion (ROM), shoulder muscle power and quality-of-life scores. In the control group, the peri-elbow volume and upper-arm volume were significantly higher post-operatively than pre-operatively. In the AWS group, no significant difference was found. In comparison with the control group, the AWS group had significantly more pain, less active ROM in shoulder abduction and a lower upper-limb volume at 0-10 cm proximal to the lateral epicondyle. The incidence of lymphedema was 9.9% and was not associated with AWS. AWS is a common morbidity of lymph node dissection and causes significant pain and restricted shoulder abduction in the affected limb in BC survivors. This study is the first to investigate post-operative upper-limb volumetric changes in BC survivors with and without AWS. Our findings are of great value for the clinical effect of AWS in BC survivors, for patient education, and for developing diagnostic tools for detecting AWS.

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.

Slug is temporally regulated by cyclin E in cell cycle and controls genome stability.

The transcriptional repressor Slug is best known to control epithelial-mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.