Lactate dehydrogenase A(LDHA)is an important enzyme involved in the anaerobic glycolysis of cells,catalyzing the conversion of pyruvate to lactate and participating in processes such as tumor proliferation,mi-gration,invasion,and the regulation of the tumor microenvironment.High expression levels of LDHA are often in-dicative of disease progression and poor prognosis in malignant hematological diseases.The expression of LDHA in malignant hematological diseases is closely associated with various molecules,including HIF-1,microRNAs and c-Myc,as well as signaling pathways like PI3K/AKT/GSK3,USP1/PLK1/LDHA and Fbw7/LDHA/lactate/miR-223.Meanwhile,the progression of malignant hematological conditions facilitated by LDHA primarily occurs through the regulation of energy metabolism via glycolytic pathways.

Objective To study the dynamic regulatory role of early growth response 4(EGR4)in mouse neurodevelopment.Methods Data on single-cell chromatin accessibility(single-cell assay for transposase-accessible chromatin by sequencing,scATAC-seq)and transcriptome(single-cell RNA sequencing,scRNA-seq)from seven key stages spanning from the embryonic period to adulthood was collected and analyzed.The transcription factor binding site network was inferred,a quantitative analysis from a temporal perspective was conducted,its functional modules were parsed,and the results were visualized.Results egr4 was significantly highly expressed from the late embryonic stage to adulthood,and specifically activated during the maturation of inhibitory neurons[parvalbumin(PV)and somatostatin(SST)subtypes].Moreover,its transcription was not directly regulated by changes in chromatin accessibility.Temporal network analysis indicated that EGR4 became a regulatory hub in the late embryonic stage and drove neuron differentiation and subtype specification.Functional enrichment analysis showed that EGR4 regulated the"cell differentiation"pathway through dynamic interacting factors,and there were subtype-specific interaction modules in PV/SST neurons respectively.Conclusion EGR4 can participate in the late-stage maturation of cortical neurons through a stage-specific regulatory network.This study provides a new perspective on mechanisms underlying the temporal logic of neural development.

Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα⁺) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα⁺ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒ 29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

Objective To investigate the risk distribution of breast cancer for location and time of recurrence metastasis in molecular subtype.Methods We studied retrospectively the female patients who were diagnosed as invasive ductal breast cancer in our hospital from July 2004 to June 2012,detected ER,PR,and HER2 expressions in the paraffin sections.The patients with recurrence metastasis were divided into local recurrence and distant metastasis with the first transfer site as standard for analyzing the distribution in molecular subtype and the time of the first site of recurrence metastasis.Results Sixty two patients were encountered recurrence metastasis,including 23 patients with local recurrence,and 39 patients with distant metastasis,death 11.The rates of distant metastasis for patients who belonged to HER2 type and basal-like type were higher than that of local recurrence (P =0.01,P =0.001).The risk distribution of recurrence metastasis time in molecular recurrence metastasis showed that 35 percent of recurrence metastasis time of luminal A type was first 3 years,75 percent of molecular subtype of basa1-1ike type recurrence metastasis time in first 3 years and advanced.The peak of luminal B and HER2 type was first 3 years,and very low in 5 years.Conclusions Molecular subtype of breast cancer is an important complement for TNM method in accurately assessing the patients of recurrence metastasis for location and time,and is helpful for the individual screening of patients for recurrence metastasis.

Objective:To establish and validate the rat model of syndrome of stagnation of liver qi,followed by a primary study on this model with 1H NMR based on metabonomics to explore the essence of syndrome of stagnation of liver qi. Methods:Twelve Wistar male rats were randomly divided into two groups(model group and control group).The rats of model group were restrained by special equipment for 21 days to get into stagnation of liver qi.The behavior,fluid consumption test and plasma CORT of rats were recorded.At 22th day,animals were sacrificed and biopsies of gastric mucosa and adrenal gland were collected for pathological check,and serum samples for 1H NMR spectroscopy.The NMR data were analyzed using principal component analysis.Results:There were abnormal behaviors,such as decrease of elusion,slackness,looser stools,and matte fur were observed among model group rats.After one week the body weight of model group was significantly lower than that of control group(P