The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator ...with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.
Antiretroviral monotherapy and treatment interruption are potential strategies for perinatally HIV-infected adolescents (PHIVA) who face challenges maintaining effective combination antiretroviral ...therapy (ART). We assessed the use and outcomes for adolescents receiving monotherapy or undergoing treatment interruption in a regional Asian cohort.
Regional Asian data (2001–2016) were analyzed to describe PHIVA who experienced ≥2 weeks of lamivudine or emtricitabine monotherapy or treatment interruption and trends in CD4 count and HIV viral load during and after episodes. Survival analyses were used for World Health Organization (WHO) stage III/IV clinical and immunologic event-free survival during monotherapy or treatment interruption, and a Poisson regression to determine factors associated with monotherapy or treatment interruption.
Of 3,448 PHIVA, 84 (2.4%) experienced 94 monotherapy episodes, and 147 (4.3%) experienced 174 treatment interruptions. Monotherapy was associated with older age, HIV RNA >400 copies/mL, younger age at ART initiation, and exposure to ≥2 combination ART regimens. Treatment interruption was associated with CD4 count <350 cells/μL, HIV RNA ≥1,000 copies/mL, ART adverse event, and commencing ART age ≥10 years compared with age <3 years. WHO clinical stage III/IV 1-year event-free survival was 96% and 85% for monotherapy and treatment interruption cohorts, respectively. WHO immunologic stage III/IV 1-year event-free survival was 52% for both cohorts. Those who experienced monotherapy or treatment interruption for more than 6 months had worse immunologic and virologic outcomes.
Until challenges of treatment adherence, engagement in care, and combination ART durability/tolerability are met, monotherapy and treatment interruption will lead to poor long-term outcomes.
BACKGROUND:Perinatally HIV-infected adolescents (PHIVA) are an expanding population vulnerable to loss to follow-up (LTFU). Understanding the epidemiology and factors for LTFU is complicated by ...varying LTFU definitions.
SETTING:Asian regional cohort incorporating 16 pediatric HIV services across 6 countries.
METHODS:Data from PHIVA (aged 10–19 years) who received combination antiretroviral therapy 2007–2016 were used to analyze LTFU through (1) an International epidemiology Databases to Evaluate AIDS (IeDEA) method that determined LTFU as >90 days late for an estimated next scheduled appointment without returning to care and (2) the absence of patient-level data for >365 days before the last data transfer from clinic sites. Descriptive analyses and competing-risk survival and regression analyses were used to evaluate LTFU epidemiology and associated factors when analyzed using each method.
RESULTS:Of 3509 included PHIVA, 275 (7.8%) met IeDEA and 149 (4.3%) met 365-day absence LTFU criteria. Cumulative incidence of LTFU was 19.9% and 11.8% using IeDEA and 365-day absence criteria, respectively. Risk factors for LTFU across both criteria included the followingage at combination antiretroviral therapy initiation <5 years compared with age ≥5 years, rural clinic settings compared with urban clinic settings, and high viral loads compared with undetectable viral loads. Age 10–14 years compared with age 15–19 years was another risk factor identified using 365-day absence criteria but not IeDEA LTFU criteria.
CONCLUSIONS:Between 12% and 20% of PHIVA were determined LTFU with treatment fatigue and rural treatment settings consistent risk factors. Better tracking of adolescents is required to provide a definitive understanding of LTFU and optimize evidence-based models of care.
BACKGROUND:Information on antiretroviral therapy (ART) use in HIV-infected children with severe malnutrition (SM) is lacking. We investigated long-term ART outcomes in this population.
...METHODS:Children enrolled in the TREAT Asia Pediatric HIV Observational Database who had SM (weight-for-height or body mass index–for-age Z score less than −3) at ART initiation were analyzed. Generalized estimating equations were used to investigate poor weight recovery (weight-for-age Z score less than −3) and poor CD4% recovery (CD4% <25), and competing risk regression was used to analyze mortality and toxicity-associated treatment modification.
RESULTS:Three hundred fifty-five (11.9%) of 2993 children starting ART had SM. Their median weight-for-age Z score increased from −5.6 at ART initiation to −2.3 after 36 months. Not using trimethoprim–sulfamethoxazole prophylaxis at baseline was associated with poor weight recovery odds ratio2.49 vs. using; 95% confidence interval (CI)1.66–3.74; P < 0.001. Median CD4% increased from 3.0 at ART initiation to 27.2 after 36 months, and 56 (15.3%) children died during follow-up. More profound SM was associated with poor CD4% recovery (odds ratio1.78 for Z score less than −4.5 vs. −3.5 to less than −3.0; 95% CI1.08–2.92; P = 0.023) and mortality (hazard ratio2.57 for Z score less than −4.5 vs. −3.5 to less than −3.0; 95% CI1.24–5.33; P = 0.011). Twenty-two toxicity-associated ART modifications occurred at a rate of 2.4 per 100 patient-years, and rates did not differ by malnutrition severity.
CONCLUSION:Trimethoprim–sulfamethoxazole prophylaxis is important for the recovery of weight-for-age in severely malnourished children starting ART. The extent of SM does not impede weight-for-age recovery or antiretroviral tolerability, but CD4% response is compromised in children with a very low weight-for-height/body mass index-for-age Z score, which may contribute to their high rate of mortality.
Screening expressed sequence tag databases for endothelial-specific homologs to human junctional adhesion molecule (JAM) and A33-Ag, we identified a protein of 298 aa that represents the recently ...described vascular endothelial-JAM (VE-JAM)/JAM 2. We confirmed VE-JAM/JAM 2 expression to be restricted to the high endothelial venule of tonsil and lymph nodes, and we further expanded the localization to the endothelium of arterioles in and around inflammatory and tumor foci. In our functional characterizations of VE-JAM/JAM 2, we discovered that it can function as an adhesive ligand for the T cell line J45 and can interact with GM-CSF/IL-4-derived peripheral blood dendritic cells, circulating CD56(+) NK cells, circulating CD56(+)CD3(+) NK/T cells, and circulating CD56(+)CD3(+)CD8(+) cytolytic T cells. In the course of our studies, we also isolated and characterized the functional VE-JAM/JAM 2 receptor, which, upon cloning, turned out to be a submitted sequence representing JAM 3 (accession number NP 113658). With these understandings, we have characterized a protein-interacting pair that can be important in the role of T, NK, and dendritic cell trafficking and inflammation.
Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse C57MG cells to isolate mRNAs induced by Wnt-1 ...and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor-gamma-responsive genes in human cancers.
A 16 Gb 8-level NAND flash chip on 56 nm CMOS technology has been fabricated and is being reported for the first time. This is the first 3-bit per cell (X3) chip published with all-bitline (ABL) ...architecture, which doubles the write performance compared with conventional shielded bitline architecture. A new advanced cache program algorithm provides another 15% improvement in write performance. This paper also discusses a technique for resolving the sensing error resulting from cell source line noise, which usually varies with the data pattern. The new architecture and advanced algorithm enable an 8 MB/s write performance that is comparable to previously published 2-bit per cell (4-level) NAND performance. Considering the significant cost reduction compared to 4-level NAND flash based on the same technology, this chip is a strong candidate for many mainstream applications.
Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon ...strength. The authors hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing.
To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis.
Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, the authors also found up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with the authors' microarray data.
The authors demonstrate an overall antifibrotic expression pattern in response to shear stress in tendon cells that may provide insight into the mechanisms by which early mobilization decreases adhesion formation without impaired tendon healing.
An 8-Gb multi-level NAND Flash memory with 4-level programmed cells has been developed successfully. The cost-effective small chip has been fabricated in 70-nm CMOS technology. To decrease the chip ...size, a one-sided pad arrangement with compacted core architecture and a block address expansion scheme without block redundancy replacement have been introduced. With these methods, the chip size has been reduced to 146 mm/sup 2/, which is 4.9% smaller than the conventional chip. In terms of performance, the program throughput reaches 6 MB/s at 4-KB page operation, which is significantly faster than previously reported and very competitive with binary Flash memories. This high performance has been achieved by the combination of the multi-level cell (MLC) programming with write caches and with the program voltage compensation technique for neighboring select transistors. The read throughput reaches 60 MB/s using 16I/O configuration.
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