A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.

mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy

Preparation and ageing-resistant properties of polyester composites modified with functional nanoscale additives

This study investigated ageing-resistant properties of carboxyl-terminated polyester (polyethylene glycol terephthalate) composites modified with nanoscale titanium dioxide particles (nano-TiO(2)). The nano-TiO(2) was pretreated by a dry coating method, with aluminate coupling agent as a functional grafting additive. The agglomeration resistance was evaluated, which exhibited significant improvement for the modified nanoparticles. Then, the effects of the modified nano-TiO(2) on the crosslinking and ageing-resistant properties of the composites were studied. With a real-time Fourier transform infrared (FT-IR) measurement, the nano-TiO(2) displayed promoting effect on the crosslinking of polyester resin with triglycidyl isocyanurate (TGIC) as crosslinking agent. Moreover, the gloss retention, colour aberration and the surface morphologies of the composites during accelerated UV ageing (1500 hours) were investigated. The results demonstrated much less degree of ageing degradation for the nanocomposites, indicating an important role of the nano-TiO(2) in improving the ageing-resistant properties of synthetic polymer composites

KARYOLOGICAL STUDIES OF THE HYBRID LARVAE OF HALIOTIS DISVERSICOLOR SUPERTEXTA FEMALE AND HALIOTIS DISCUS DISCUS MALE

To determine the genomic composition of the interspecific hybrid between Haliotis diversicolor supertexta female and H. discus discus male at an early developmental stage, veliger larvae produced from hybrid (SJ-5 and SJ-50) and pure species crosses (SS and JJ) were sampled and analyzed using standard karyological methods and genomic in situ hybridization. In hybrid metaphase spreads, chromosomes from both parents were detected, except one metaphase, which showed the H. diversicolor supertexta haploid karyotype. The genomic composition of the hybrid was also confirmed through preliminary genomic in situ hybridization results. Many more aneuploids and chromosome fragments were found in the hybrids than those in the control pure species crosses, indicating genome instability and chromosome loss in the hybrids. In the hybrid hypodiploid metaphase spreads, two intact sets of H. diversicolor supertexta chromosomes and several H. discus discus chromosomes were detected by pairing. Spontaneous diploidization of the maternal chromosome set was shown to occur in hybrid larvae, as 2.2% heterogeneous triploid and 17.9% hypodiploids with two intact H. diversicolor supertexta chromosome sets for SJ-5. The current findings suggest that uniparental chromosome elimination along with spontaneous diploidization of maternal chromosome sets may be the reason for allogynogenesis production in H. diversicolor supertexta X H. discus discus hybridization

Simplified HIV Testing and Treatment in China: Analysis of Mortality Rates Before and After a Structural Intervention.

BackgroundMultistage stepwise HIV testing and treatment initiation procedures can result in lost opportunities to provide timely antiretroviral therapy (ART). Incomplete patient engagement along the continuum of HIV care translates into high levels of preventable mortality. We aimed to evaluate the ability of a simplified test and treat structural intervention to reduce mortality.Methods and findingsIn the "pre-intervention 2010" (from January 2010 to December 2010) and "pre-intervention 2011" (from January 2011 to December 2011) phases, patients who screened HIV-positive at health care facilities in Zhongshan and Pubei counties in Guangxi, China, followed the standard-of-care process. In the "post-intervention 2012" (from July 2012 to June 2013) and "post-intervention 2013" (from July 2013 to June 2014) phases, patients who screened HIV-positive at the same facilities were offered a simplified test and treat intervention, i.e., concurrent HIV confirmatory and CD4 testing and immediate initiation of ART, irrespective of CD4 count. Participants were followed for 6-18 mo until the end of their study phase period. Mortality rates in the pre-intervention and post-intervention phases were compared for all HIV cases and for treatment-eligible HIV cases. A total of 1,034 HIV-positive participants (281 and 339 in the two pre-intervention phases respectively, and 215 and 199 in the two post-intervention phases respectively) were enrolled. Following the structural intervention, receipt of baseline CD4 testing within 30 d of HIV confirmation increased from 67%/61% (pre-intervention 2010/pre-intervention 2011) to 98%/97% (post-intervention 2012/post-intervention 2013) (all p < 0.001 [i.e., for all comparisons between a pre- and post-intervention phase]), and the time from HIV confirmation to ART initiation decreased from 53 d (interquartile range [IQR] 27-141)/43 d (IQR 15-113) to 5 d (IQR 2-12)/5 d (IQR 2-13) (all p < 0.001). Initiation of ART increased from 27%/49% to 91%/89% among all cases (all p < 0.001) and from 39%/62% to 94%/90% among individuals with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). Mortality decreased from 27%/27% to 10%/10% for all cases (all p < 0.001) and from 40%/35% to 13%/13% for cases with CD4 count ≤ 350 cells/mm3 or AIDS (all p < 0.001). The simplified test and treat intervention was significantly associated with decreased mortality rates compared to pre-intervention 2011 (adjusted hazard ratio [aHR] 0.385 [95% CI 0.239-0.620] and 0.380 [95% CI 0.233-0.618] for the two post-intervention phases, respectively, for all newly diagnosed HIV cases [both p < 0.001], and aHR 0.369 [95% CI 0.226-0.603] and 0.361 [95% CI 0.221-0.590] for newly diagnosed treatment-eligible HIV cases [both p < 0.001]). The unit cost of an additional patient receiving ART attributable to the intervention was US$83.80. The unit cost of a death prevented because of the intervention was US$234.52.ConclusionsOur results demonstrate that the simplified HIV test and treat intervention promoted successful engagement in care and was associated with a 62% reduction in mortality. Our findings support the implementation of integrated HIV testing and immediate access to ART irrespective of CD4 count, in order to optimize the impact of ART

Multi-agent Reinforcement Learning with Deep Networks for Diverse Q-Vectors

Multi-agent reinforcement learning (MARL) has become a significant research topic due to its ability to facilitate learning in complex environments. In multi-agent tasks, the state-action value, commonly referred to as the Q-value, can vary among agents because of their individual rewards, resulting in a Q-vector. Determining an optimal policy is challenging, as it involves more than just maximizing a single Q-value. Various optimal policies, such as a Nash equilibrium, have been studied in this context. Algorithms like Nash Q-learning and Nash Actor-Critic have shown effectiveness in these scenarios. This paper extends this research by proposing a deep Q-networks (DQN) algorithm capable of learning various Q-vectors using Max, Nash, and Maximin strategies. The effectiveness of this approach is demonstrated in an environment where dual robotic arms collaborate to lift a pot

LLM as Prompter: Low-resource Inductive Reasoning on Arbitrary Knowledge Graphs

Knowledge Graph (KG) inductive reasoning, which aims to infer missing facts from new KGs that are not seen during training, has been widely adopted in various applications. One critical challenge of KG inductive reasoning is handling low-resource scenarios with scarcity in both textual and structural aspects. In this paper, we attempt to address this challenge with Large Language Models (LLMs). Particularly, we utilize the state-of-the-art LLMs to generate a graph-structural prompt to enhance the pre-trained Graph Neural Networks (GNNs), which brings us new methodological insights into the KG inductive reasoning methods, as well as high generalizability in practice. On the methodological side, we introduce a novel pretraining and prompting framework ProLINK, designed for low-resource inductive reasoning across arbitrary KGs without requiring additional training. On the practical side, we experimentally evaluate our approach on 36 low-resource KG datasets and find that ProLINK outperforms previous methods in three-shot, one-shot, and zero-shot reasoning tasks, exhibiting average performance improvements by 20%, 45%, and 147%, respectively. Furthermore, ProLINK demonstrates strong robustness for various LLM promptings as well as full-shot scenarios.Comment: Accepted by Findings of ACL202