Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia.

Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKis

A Rare Case of Richter Transformation to Both Clonally Unrelated and Clonally Related Diffuse Large B-Cell Lymphoma in the Same Patient.

Richter transformation (RT) is a rare sequelae of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The clonal relationship of the RT to the underlined CLL/SLL is an important prognostic factor as clonally related RT has a worse prognosis than that of clonally unrelated RT. The development of more than one RT in the same patient is exceedingly rare and prior reports have shown cases consisting of RT to diffuse large B-cell lymphoma (DLBCL) and a subsequent or synchronous Hodgkin lymphoma. Here, we present a rare case of RT first to a clonally unrelated DLBCL and subsequently a clonally related DLBCL. Additionally, we retrospectively conducted next-generation sequencing studies of both RTs and found different mutational landscapes, including more clinically aggressive mutations identified in the clonally related RT. To our knowledge, this is the first reported case of clonally related and clonally unrelated RT, both of which are DLBCL, in the same patient

Exploring the Applicability of Building Energy Performance Certification Systems in Underground Stations in China

To improve the energy efficiency of underground metro stations, and in view of the absence of a comprehensive energy performance evaluation system for underground stations, this study introduced building Energy Performance Certification (EPC) tools into underground stations and conducted a comparative analysis of their applicability. The findings indicated that due to the unique characteristics of underground stations, China’s current EPC system was inapplicable to them. Specifically, (1) for basic items, although evaluation methods were available, due to the limited energy use data for the statistical method, the self-reference method was preferred, but its calculation encountered issues with missing reference values; (2) for prescribed items, the emphasis should be placed on the energy efficiency requirements of energy use systems rather than those of the thermal performance of envelopes; (3) for alternative items, the energy recovery measures related to the heat dissipation of trains and the piston wind should be addressed. Furthermore, a case study was conducted for verification of the proposed energy evaluation method, and the EPC system was updated based on the results of the comparison. The authors hope that this study will help improve China’s energy evaluation methods for underground stations and serve as a reference for expanding the EPC system to include public transportation buildings

Towards Understanding Chain-of-Thought Prompting: An Empirical Study of What Matters

Chain-of-Thought (CoT) prompting can dramatically improve the multi-step reasoning abilities of large language models (LLMs). CoT explicitly encourages the LLM to generate intermediate rationales for solving a problem, by providing a series of reasoning steps in the demonstrations. Despite its success, there is still little understanding of what makes CoT prompting effective and which aspects of the demonstrated reasoning steps contribute to its performance. In this paper, we show that CoT reasoning is possible even with invalid demonstrations - prompting with invalid reasoning steps can achieve over 80-90% of the performance obtained using CoT under various metrics, while still generating coherent lines of reasoning during inference. Further experiments show that other aspects of the rationales, such as being relevant to the query and correctly ordering the reasoning steps, are much more important for effective CoT reasoning. Overall, these findings both deepen our understanding of CoT prompting, and open up new questions regarding LLMs' capability to learn to reason in context.Comment: ACL-23 Camera Ready. Code and model input/output are available at https://github.com/sunlab-osu/Understanding-Co