Presbyopia, age-related decline in near vision, is the most common cause of vision impairment globally, but no trials have assessed its workplace effects. We aimed to study the effect of near glasses on the productivity of tea workers with presbyopia. This randomised trial was done in tea pickers aged 40 years or older in Assam, India, with unaided near visual acuity (NVA) lower than 6/12 in both eyes, correctable to 6/7·5 with near glasses; unaided distance vision 6/7·5 or greater; and no eye disease. Participants were randomly assigned (1:1) to receive free glasses optimising NVA at working distance (cost including delivery US$10·20 per person), either immediately (intervention group) or at closeout (control group). Participants were stratified by age, sex, and productivity. The primary outcome (investigator-masked) was the difference between groups in the change in mean daily weight of tea picked (productivity), between the 4-week baseline period (June, 2017) and the 11-week evaluation period (July 24, 2017, to Oct 7, 2017). Workers' income was tied to their productivity. Compliance with study glasses was assessed at seven unannounced visits. Results were analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT03228199. Between July 3, 2017, and July 15, 2017, 1297 (48·1%) of 2699 permanent workers met the age criteria and consented for eye examinations. 751 (57·9%) fulfilled vision criteria and were randomly assigned to the intervention (n=376) or control (n=375) groups. Groups did not differ substantially in baseline characteristics. No participants owned glasses at baseline, 707 (94·1%) received the allocated intervention, and all were followed up and analysed. Between the baseline and evaluation periods, mean productivity in the intervention group increased from 25·0 kg per day to 34·8 kg per day (an increase of 9·84 kg per day), a significantly higher increase than in the control group (from 26·0 kg per day to 30·6 kg per day; an increase of 4·59 kg per day), corresponding to a between-group difference of 5·25 kg per day (95% CI 4·50-5·99; 21·7% relative productivity increase; effect size 1·01 [95% CI 0·86-1·16]; p<0·0001). Intervention-group compliance with study glasses reached 84·5% by closeout. Regression model predictors of greater productivity increase included intervention group membership (5·25 kg per day [95% CI 4·60-5·91], p<0·0001) and, among intervention participants, older age (p=0·039) and better compliance with the intervention (p<0·0001). A substantial productivity increase was achieved in this rural cohort by providing glasses to correct presbyopia, with little cost and high intervention uptake. Clearly.

DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients.

The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth. Cancer Res; 77(18); 4921–33. ©2017 AACR.

Osteopontin (OPN) plays an important role in cancer progression, however its prognostic significance and its downstream factors are largely elusive. In this study, we have shown that expression of OPN was significantly higher in bladder cancer specimens with higher T-stage or tumor grades. In addition, a high level of OPN was significantly associated with poorer survival in two independent bladder cancer patient cohorts totaling 389 bladder cancer patients with available survival data. We further identified Matrix metallopeptidase 9 (MMP9) and S100 calcium-binding protein A8 (S100A8) were both downstream factors for OPN in bladder cancer specimens and bladder cancer cell lines. Expression of OPN was significantly positively associated with that of MMP9 and S100A8, while overexpression of OPN resulted in upregulation of MMP9 and S100A8, and knockdown of OPN showed consistent downregulation of MMP9 and S100A8 expression levels. Importantly, expression levels of both MMP9 and S100A8 were significantly associated with higher T-stage, higher tumor grade and a shorter survival time in the bladder cancer patients. Interestingly, OPN expression only predicted survival in MMP9-high, but not MMP9-low subgroups, and in S100A8-low but not S100A8-high subgroups. Our results suggest that OPN, MMP9 and S100A8 all play a significant role in bladder cancer progression and are potential prognostic markers and therapeutic targets in bladder cancer. The mechanistic link between these three genes and bladder cancer progression warrants further investigation.

β-defensin family plays a role in host defense against viral infection, however its role in HCV infection is still unknown. In this study, we demonstrated that β-defensin 1 was significantly reduced in HCV-infected liver specimens. Treatment with interferon and ribavirin upregulated β-defensin-1, but not other β-defensin tested, with the extent and duration of upregulation associated with treatment response. We investigated β-defensin family expression in liver cancer in publicly available datasets and found that among all the β-defensins tested, only β-defensin 1 was significantly downregulated, suggesting β-defensin 1 plays a crucial role in liver cancer development. Further analysis identified E-cadherin as the top positive correlated gene, while hepatocyte growth factor-regulated tyrosine kinase substrate as the top negative correlated gene. Expression of two proteoglycans were also positively correlated with that of β-defensin 1. We have also identified small molecules as potential therapeutic agents to reverse β-defensin 1-associated gene signature. Furthermore, the downregulation of β-defensin 1 and E-cadherin, and upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate, were further confirmed in liver cancer and adjacent normal tissue collected from in-house Chinese liver cancer patients. Together, our results suggest β-defensin 1 plays an important role in protecting HCV progression and liver cancer development.