The nucleophosmin 1(NPM1)muta-tion is one of the most frequent subtypes in acute myeloid leukemia(AML).Under the conditions of FLT3-internal tandem duplications(FLT3-ITD)and/or DNMT3A co-mutations or adverse cytogenetics,the originally favorable prognosis will deteriorate.In recent years,studies have found that multiple endocrine neoplasia protein(Menin)inhibitors tar-geting Menin-KMT2A complex can downregulate the overexpression of leukemia causing genes HOX(homeotic gene)and MEIS1(myeloid ecotropic vi-ral integration site 1)in NPM1-mutated AML,dem-onstrating remarkable anti-leukemia activity.This article aims to review the mechanism and clinical research of Menin inhibitors,novel small molecule targeted drugs in NPM1-mutated AML,as well as the resistance mechanism of Menin inhibitors,hop-ing to provide promising approaches for the subse-quent treatment of NPM1-mutated AML patients.

The nucleophosmin 1(NPM1)muta-tion is one of the most frequent subtypes in acute myeloid leukemia(AML).Under the conditions of FLT3-internal tandem duplications(FLT3-ITD)and/or DNMT3A co-mutations or adverse cytogenetics,the originally favorable prognosis will deteriorate.In recent years,studies have found that multiple endocrine neoplasia protein(Menin)inhibitors tar-geting Menin-KMT2A complex can downregulate the overexpression of leukemia causing genes HOX(homeotic gene)and MEIS1(myeloid ecotropic vi-ral integration site 1)in NPM1-mutated AML,dem-onstrating remarkable anti-leukemia activity.This article aims to review the mechanism and clinical research of Menin inhibitors,novel small molecule targeted drugs in NPM1-mutated AML,as well as the resistance mechanism of Menin inhibitors,hop-ing to provide promising approaches for the subse-quent treatment of NPM1-mutated AML patients.

BACKGROUND:Some patients still have unsatisfactory improvement of operative limb fatigue and pain after total knee arthroplasty.Clinical findings show that Jianpi Yiqi Huoxue Formula can promote recovery after total knee arthroplasty,but the specific efficacy remains to be studied. OBJECTIVE:To observe the effect of Jianpi Yiqi Huoxue Formula on the muscle strength and pain of the operated limb after the primary unilateral total knee arthroplasty. METHODS:A total of 74 patients undergoing primary unilateral total knee arthroplasty were randomly divided into a trial group and a control group with 37 patients in each group.All patients received the same prostheses and surgical methods during the operation.Patients in the control group were treated with routine analgesics,anticoagulant drugs and functional exercise after the operation.The trial group received Jianpi Yiqi Huoxue Formula after the treatment in the control group.Both groups were treated continuously and followed up for 1 month.The changes in isokinetic muscle strength(peak torque and total work amount of extensor and flexor),visual analog scale score and the hospital for special surgery score of the two groups were analyzed. RESULTS AND CONCLUSION:(1)The trial group had better improvement in peak torque and total work amount of extensor and flexor and the hospital for special surgery score than the control group 14 days and 1 month after surgery(P<0.05).(2)In contrast to the control group,the visual analog scale score of the trial group improved better at 7 and 14 days and 1 month after surgery(P<0.05).(3)It is indicated that Jianpi Yiqi Huoxue Formula can effectively improve the muscle strength of the operated limb,enhance the degree of postoperative joint pain,and promote functional rehabilitation after total knee arthroplasty.

BACKGROUND:MRI is important for the diagnosis of early knee osteoarthritis.MRI image recognition and intelligent segmentation of knee osteoarthritis using deep learning method is a hot topic in image diagnosis of artificial intelligence. OBJECTIVE:Through deep learning of MRI images of knee osteoarthritis,the segmentation of femur,tibia,patella,cartilage,meniscus,ligaments,muscles and effusion of knee can be automatically divided,and then volume of knee fluid and muscle content were measured. METHODS:100 normal knee joints and 100 knee osteoarthritis patients were selected and randomly divided into training dataset(n=160),validation dataset(n=20),and test dataset(n=20)according to the ratio of 8:1:1.The Coarse-to-Fine sequential training method was used to train the 3D-UNET network deep learning model.A Coarse MRI segmentation model of the knee sagittal plane was trained first,and the rough segmentation results were used as a mask,and then the fine segmentation model was trained.The T1WI and T2WI images of the sagittal surface of the knee joint and the marking files of each structure were input,and DeepLab v3 was used to segment bone,cartilage,ligament,meniscus,muscle,and effusion of knee,and 3D reconstruction was finally displayed and automatic measurement results(muscle content and volume of knee fluid)were displayed to complete the deep learning application program.The MRI data of 26 normal subjects and 38 patients with knee osteoarthritis were screened for validation. RESULTS AND CONCLUSION:(1)The 26 normal subjects were selected,including 13 females and 13 males,with a mean age of(34.88±11.75)years old.The mean muscle content of the knee joint was(1 051 322.94±2 007 249.00)mL,the mean median was 631 165.21 mL,and the mean volume of effusion was(291.85±559.59)mL.The mean median was 0 mL.(2)There were 38 patients with knee osteoarthritis,including 30 females and 8 males.The mean age was(68.53±9.87)years old.The mean muscle content was(782 409.18±331 392.56)mL,the mean median was 689 105.66 mL,and the mean volume of effusion was(1 625.23±5 014.03)mL.The mean median was 178.72 mL.(3)There was no significant difference in muscle content between normal people and knee osteoarthritis patients.The volume of effusion in patients with knee osteoarthritis was higher than that in normal subjects,and the difference was significant(P<0.05).(4)It is indicated that the intelligent segmentation of MRI images by deep learning can discard the defects of manual segmentation in the past.The more accuracy evaluation of knee osteoarthritis was necessary,and the image segmentation was processed more precisely in the future to improve the accuracy of the results.

Myelodysplastic syndrome(MDS)is a heterogeneous myeloid tumor that originates from hematopoietic stem cells(HSCs)and is associated with a high risk of progression to acute myeloid leukemia(AML).Studies have shown that 90%of patients with MDS have gene mutations,of whom approximately 25%have SF3B1 mutations.In patients with MDS carrying this mutation,the TGF-β pathway is upregu-lated,inducing cell cycle arrest and thereby leading to erythroid ineffective hematopoiesis and pathological hematopoiesis.Luspatercept can be used as a ligand trap to capture TGF-β ligands,inhibit SMAD2/3 pathway activation,downregulate TGF-β pathway,and promote ad-vanced red blood cell maturation.Currently,it has been approved by the Food and Drug Administration(FDA)for the treatment of anemia in patients with low-risk MDS,and studies have shown that the response rate is higher in patients with SF3B1 mutations.This article will re-view the current status of luspatercept in the treatment of SF3B1 mutation-related MDS;it will also analyze its effectiveness and safety and provide therapeutic strategies for clinical use.

Objective:To investigate the heterogeneity of FLT3 mutations and the consequences of co-occurring mutations on the clinical features and prognosis of patients with acute myeloid leukemia(AML).Methods:We retrospectively analyzed the clinical characteristics of 80 patients with AML who carried FLT3 mutations,as detected by genetic testing,and were treated in The First Hospital of Lanzhou Uni-versity from October 2017 to March 2024.An analysis was performed to evaluate the impact of FLT3 mutation frequency,insertion length of base pairs,insertion site,and co-occurring mutations on survival outcomes.Results:The variant allele frequency(VAF)of FLT3-ITD muta-tions was correlated with leukocyte counts and lactate dehydrogenase levels in patients with de novo AML.There was an association between the insertion site and the length of the base-pair insertion.Patients with AML who also had a VAF of FLT3-ITD mutations greater than or equal to 0.38 exhibit reduced overall survival(OS),whereas the length of base pair insertion,insertion site,and number of muta-tions did not correlate with OS.Patients with non-classical FLT3 mutations demonstrated a significantly longer OS than did those with FLT3-ITD mutations.The co-occurrence of FLT3-ITD,NPM1,and DNMT3A mutations was associated with markedly reduced OS.The use of FLT3 inhibitors and allogeneic hematopoietic stem cell transplantation(allo-HSCT)can improve the prognosis of patients with FLT3-ITD mutations.Conclusions:FLT3 mutational heterogeneity correlates with the clinical characteristics and outcomes of patients with AML.Non-classical FLT3 and FLT3-TKD mutations are associated with superior prognosis.Patients with a VAF of 0.38 or higher have a poorer prognosis,but the use of FLT3 inhibitors can improve their prognosis.Patients with triple mutations have poor prognosis.

Knowledge about the neuronal dynamics and the projectome are both essential for understanding how the neuronal network functions in concert. However, it remains challenging to obtain the neural activity and the brain-wide projectome for the same neurons, especially for neurons in subcortical brain regions. Here, by combining in vivo microscopy and high-definition fluorescence micro-optical sectioning tomography, we have developed strategies for mapping the brain-wide projectome of functionally relevant neurons in the somatosensory cortex, the dorsal hippocampus, and the substantia nigra pars compacta. More importantly, we also developed a strategy to achieve acquiring the neural dynamic and brain-wide projectome of the molecularly defined neuronal subtype. The strategies developed in this study solved the essential problem of linking brain-wide projectome to neuronal dynamics for neurons in subcortical structures and provided valuable approaches for understanding how the brain is functionally organized via intricate connectivity patterns.
Animals ; Neurons/physiology* ; Mice ; Brain/physiology* ; Mice, Inbred C57BL ; Somatosensory Cortex/physiology* ; Neural Pathways/physiology* ; Hippocampus/physiology* ; Mice, Transgenic ; Male ; Brain Mapping ; Nerve Net/physiology* ; Substantia Nigra/physiology* ; Tomography, Optical/methods*

Objective:To investigate the heterogeneity of FLT3 mutations and the consequences of co-occurring mutations on the clinical features and prognosis of patients with acute myeloid leukemia(AML).Methods:We retrospectively analyzed the clinical characteristics of 80 patients with AML who carried FLT3 mutations,as detected by genetic testing,and were treated in The First Hospital of Lanzhou Uni-versity from October 2017 to March 2024.An analysis was performed to evaluate the impact of FLT3 mutation frequency,insertion length of base pairs,insertion site,and co-occurring mutations on survival outcomes.Results:The variant allele frequency(VAF)of FLT3-ITD muta-tions was correlated with leukocyte counts and lactate dehydrogenase levels in patients with de novo AML.There was an association between the insertion site and the length of the base-pair insertion.Patients with AML who also had a VAF of FLT3-ITD mutations greater than or equal to 0.38 exhibit reduced overall survival(OS),whereas the length of base pair insertion,insertion site,and number of muta-tions did not correlate with OS.Patients with non-classical FLT3 mutations demonstrated a significantly longer OS than did those with FLT3-ITD mutations.The co-occurrence of FLT3-ITD,NPM1,and DNMT3A mutations was associated with markedly reduced OS.The use of FLT3 inhibitors and allogeneic hematopoietic stem cell transplantation(allo-HSCT)can improve the prognosis of patients with FLT3-ITD mutations.Conclusions:FLT3 mutational heterogeneity correlates with the clinical characteristics and outcomes of patients with AML.Non-classical FLT3 and FLT3-TKD mutations are associated with superior prognosis.Patients with a VAF of 0.38 or higher have a poorer prognosis,but the use of FLT3 inhibitors can improve their prognosis.Patients with triple mutations have poor prognosis.

Neurons in the primary auditory area (AUDp) innervate multiple brain regions with long-range projections while receiving informative inputs for diverse functions. However, the brain-wide connections of these neurons have not been comprehensively investigated. Here, we simultaneously applied virus-based anterograde and retrograde tracing, labeled the connections of excitatory and inhibitory neurons in the mouse AUDp, and acquired whole-brain information using a dual-channel fluorescence micro-optical sectioning tomography system. Quantified results showed that the two types of neurons received inputs with similar patterns but sent heterogeneous projections to downstream regions. In the isocortex, functionally different areas consistently sent feedback-dominated projections to these neurons, with concomitant laterally-dominated projections from the sensory and limbic cortices to inhibitory neurons. In subcortical regions, the dorsal and medial parts of the non-lemniscal auditory thalamus (AT) were reciprocally connected to the AUDp, while the ventral part contained the most fibers of passage from the excitatory neurons and barely sent projections back, indicating the regional heterogeneity of the AUDp-AT circuit. Our results reveal details of the whole-brain network and provide new insights for further physiological and functional studies of the AUDp.

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1^KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1^KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABA_A receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1^KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.
Animals ; Disease Models, Animal ; Fragile X Mental Retardation Protein/metabolism* ; Fragile X Syndrome/metabolism* ; Humans ; Mice ; Mice, Knockout ; Neurons/metabolism*