Birth and death of cellular senescence

Cellular senescence is a stress response of stable growth arrest mediated by the CDK inhibitors p16 and p21 which acts as a potent barrier to tumorigenesis. Senescent cells are characterized by a persistent DNA damage response and by an hypersecretory phenotypes (SASP). The SASP covers beneficial tissue repair and tumor suppressive functions, but can drive pathology, including cancer, when senescent cells are aberrantly induced and become chronic. For example, senescent cells accumulate as a consequence of cancer therapy and natural aging, and their genetic or pharmacological clearance is sufficient to extend reduce dysfunctions and extend healthy lifespan. Chapter 1 of this thesis reflects on the various contexts where senescent cells act detrimentally. Chapter 2 focuses on cancer therapy and provides detailed information on the cellular and organismal consequence of chemotherapy, radiotherapy and CDK4/6 inhibitors. Chapter 3 investigates the pro-senescence effect of CDK4/6 inhibitors and emphasizes the existence of heterogeneous senescence programs with differential consequences on health. Chapter 4 concentrates on natural aging and analyze the accumulation of p16+ senescent cells in mice and humans. Chapter 5 studies potential mechanisms regulating premature or natural accumulation of senescent cells, and also analyzes the potential influence of various intrinsic and extrinsic factors. Finally, chapter 6 represents a reflection on how the finding and knowledge developed during my PhD can contribute to the field of senescence, and how they can be used for future research efforts aimed at defining the multifactorial and heterogeneous biological roles of cellular senescence

The Quest to Define and Target Cellular Senescence in Cancer

Cellular senescence represents a double-edged sword in cancer and its therapy. On one side, senescence-associated growth arrest and immunomodulatory properties exert potent antimalignant functions. On the other side, senescence bypass and secretory phenotype are associated with tumor progression and relapse. Recent studies have demonstrated the enormous potential to combine pro- to antisenescence interventions as a new anticancer approach. However, the heterogeneity of senescence-associated features makes definition and targeting of therapy-induced senescent cells a challenging task. Here, we describe these challenges and discuss how to exploit senescence-associated features to improve treatment efficacy and tolerability

Can ChatGPT Defend its Belief in Truth? Evaluating LLM Reasoning via Debate

Large language models (LLMs) such as ChatGPT and GPT-4 have shown impressive performance in complex reasoning tasks. However, it is difficult to know whether the models are reasoning based on deep understandings of truth and logic, or leveraging their memorized patterns in a relatively superficial way. In this work, we explore testing LLMs' reasoning by engaging with them in a debate-like conversation, where given a question, the LLM and the user need to discuss to make the correct decision starting from opposing arguments. Upon mitigating the Clever Hans effect, our task requires the LLM to not only achieve the correct answer on its own, but also be able to hold and defend its belief instead of blindly believing or getting misled by the user's (invalid) arguments and critiques, thus testing in greater depth whether the LLM grasps the essence of the reasoning required to solve the problem. Across a range of complex reasoning benchmarks spanning math, commonsense, logic and BIG-Bench tasks, we find that despite their impressive performance as reported in existing work on generating correct step-by-step solutions in the beginning, LLMs like ChatGPT cannot maintain their beliefs in truth for a significant portion of examples when challenged by oftentimes absurdly invalid arguments. Our work points to danger zones of model alignment, and also suggests more careful treatments and interpretations of the recent findings that LLMs can improve their responses based on feedback.Comment: EMNLP-23 (findings

Senescent Cells in Cancer Therapy:Friends or Foes?

Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are able to potentiate various aspects of tumorigenesis, including proliferation, metastasis, and immunosuppression. Moreover, the accumulation and persistence of therapy-induced senescent cells can promote tissue dysfunction and the early onset of various age-related symptoms in treated cancer patients. Here, we review in detail the mechanisms by which cellular senescence contributes to cancer development and the side effects of cancer therapies. We also review how pharmacological interventions to eliminate senescent cells or inhibit SASP production can mitigate these negative effects and propose therapeutic strategies based on the age of the patient

Stable Score Distillation for High-Quality 3D Generation

Although Score Distillation Sampling (SDS) has exhibited remarkable performance in conditional 3D content generation, a comprehensive understanding of its formulation is still lacking, hindering the development of 3D generation. In this work, we decompose SDS as a combination of three functional components, namely mode-seeking, mode-disengaging and variance-reducing terms, analyzing the properties of each. We show that problems such as over-smoothness and implausibility result from the intrinsic deficiency of the first two terms and propose a more advanced variance-reducing term than that introduced by SDS. Based on the analysis, we propose a simple yet effective approach named Stable Score Distillation (SSD) which strategically orchestrates each term for high-quality 3D generation and can be readily incorporated to various 3D generation frameworks and 3D representations. Extensive experiments validate the efficacy of our approach, demonstrating its ability to generate high-fidelity 3D content without succumbing to issues such as over-smoothness

How Trustworthy are Open-Source LLMs? An Assessment under Malicious Demonstrations Shows their Vulnerabilities

The rapid progress in open-source Large Language Models (LLMs) is significantly driving AI development forward. However, there is still a limited understanding of their trustworthiness. Deploying these models at scale without sufficient trustworthiness can pose significant risks, highlighting the need to uncover these issues promptly. In this work, we conduct an adversarial assessment of open-source LLMs on trustworthiness, scrutinizing them across eight different aspects including toxicity, stereotypes, ethics, hallucination, fairness, sycophancy, privacy, and robustness against adversarial demonstrations. We propose advCoU, an extended Chain of Utterances-based (CoU) prompting strategy by incorporating carefully crafted malicious demonstrations for trustworthiness attack. Our extensive experiments encompass recent and representative series of open-source LLMs, including Vicuna, MPT, Falcon, Mistral, and Llama 2. The empirical outcomes underscore the efficacy of our attack strategy across diverse aspects. More interestingly, our result analysis reveals that models with superior performance in general NLP tasks do not always have greater trustworthiness; in fact, larger models can be more vulnerable to attacks. Additionally, models that have undergone instruction tuning, focusing on instruction following, tend to be more susceptible, although fine-tuning LLMs for safety alignment proves effective in mitigating adversarial trustworthiness attacks.Comment: NAACL 202

LLMs in the Imaginarium: Tool Learning through Simulated Trial and Error

Tools are essential for large language models (LLMs) to acquire up-to-date information and take consequential actions in external environments. Existing work on tool-augmented LLMs primarily focuses on the broad coverage of tools and the flexibility of adding new tools. However, a critical aspect that has surprisingly been understudied is simply how accurately an LLM uses tools for which it has been trained. We find that existing LLMs, including GPT-4 and open-source LLMs specifically fine-tuned for tool use, only reach a correctness rate in the range of 30% to 60%, far from reliable use in practice. We propose a biologically inspired method for tool-augmented LLMs, simulated trial and error (STE), that orchestrates three key mechanisms for successful tool use behaviors in the biological system: trial and error, imagination, and memory. Specifically, STE leverages an LLM's 'imagination' to simulate plausible scenarios for using a tool, after which the LLM interacts with the tool to learn from its execution feedback. Both short-term and long-term memory are employed to improve the depth and breadth of the exploration, respectively. Comprehensive experiments on ToolBench show that STE substantially improves tool learning for LLMs under both in-context learning and fine-tuning settings, bringing a boost of 46.7% to Mistral-Instruct-7B and enabling it to outperform GPT-4. We also show effective continual learning of tools via a simple experience replay strategy.Comment: Code and data available at https://github.com/microsoft/simulated-trial-and-erro

A Retrieve-and-Read Framework for Knowledge Graph Link Prediction

Knowledge graph (KG) link prediction aims to infer new facts based on existing facts in the KG. Recent studies have shown that using the graph neighborhood of a node via graph neural networks (GNNs) provides more useful information compared to just using the query information. Conventional GNNs for KG link prediction follow the standard message-passing paradigm on the entire KG, which leads to superfluous computation, over-smoothing of node representations, and also limits their expressive power. On a large scale, it becomes computationally expensive to aggregate useful information from the entire KG for inference. To address the limitations of existing KG link prediction frameworks, we propose a novel retrieve-and-read framework, which first retrieves a relevant subgraph context for the query and then jointly reasons over the context and the query with a high-capacity reader. As part of our exemplar instantiation for the new framework, we propose a novel Transformer-based GNN as the reader, which incorporates graph-based attention structure and cross-attention between query and context for deep fusion. This simple yet effective design enables the model to focus on salient context information relevant to the query. Empirical results on two standard KG link prediction datasets demonstrate the competitive performance of the proposed method. Furthermore, our analysis yields valuable insights for designing improved retrievers within the framework.Comment: Accepted to CIKM'23; Published version DOI: https://doi.org/10.1145/3583780.3614769 ;12 pages, 4 figure

Active RIS Aided ISAC Systems: Beamforming Design and Performance Analysis

This paper considers an active reconfigurable intelligent surface (RIS)-aided integrated sensing and communication (ISAC) system. We aim to maximize radar signal-to-interference-plus-noise-ratio (SINR) by jointly optimizing the beamforming matrix at the dual-function radar-communication (DFRC) base station (BS) and the reflecting coefficients at the active RIS subject to the quality of service (QoS) constraints of communication users (UE) and the transmit power constraints of active RIS and DFRC BS. To tackle the optimization problem, the majorization-minimization (MM) algorithm is applied to address the nonconvex radar SINR objective function, and the resulting quartic problem is solved by developing an semidefinite relaxation (SDR)-based approach. Moreover, we derive the scaling order of the radar SINR with a large number of reflecting elements. Next, the transmit power allocation problem and the deployment strategy of the active RIS are studied with a moderate number of reflecting elements. Finally, we validate the potential of the active RIS in ISAC systems compared to passive RIS. Additionally, we deliberate on several open problems that remain for future research.Comment: 17 pages,11 figures, accepted by IEEE TCOM.The manuscript has been revised to correct several typographical error

DreamTime: An Improved Optimization Strategy for Diffusion-Guided 3D Generation

Text-to-image diffusion models pre-trained on billions of image-text pairs have recently enabled 3D content creation by optimizing a randomly initialized differentiable 3D representation with score distillation. However, the optimization process suffers slow convergence and the resultant 3D models often exhibit two limitations: (a) quality concerns such as missing attributes and distorted shape and texture; (b) extremely low diversity comparing to text-guided image synthesis. In this paper, we show that the conflict between the 3D optimization process and uniform timestep sampling in score distillation is the main reason for these limitations. To resolve this conflict, we propose to prioritize timestep sampling with monotonically non-increasing functions, which aligns the 3D optimization process with the sampling process of diffusion model. Extensive experiments show that our simple redesign significantly improves 3D content creation with faster convergence, better quality and diversity.Comment: ICLR 202