Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

[Application of "kindergarten effect" in radiotherapy for children with tumor aged 3-5 years]. / "幼儿园效应"在3~5å²å„¿ç«¥è‚¿ç˜¤æ”¾ç–—ä¸­çš„åº”ç”¨ç ”ç©¶.

OBJECTIVES: To study the clinical application effect of "kindergarten effect" in radiotherapy for children with tumor based on the psychology of preschool children aged 3-5 years. METHODS: A total of 30 children, aged 3-5 years, who were admitted to the Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, from January 2020 to August 2021 were enrolled in this prospective study. The children were randomly divided into a control group and a test group, with 15 children in each group. The children in the test group were treated in "kindergarten mode", i.e., all children were treated together at a specified time and left together after all children completed treatment. Those in the control group were treated alternately with adult patients according to the treatment time based on the type of radiotherapy fixation device. The treatment compliance was evaluated for both groups, and the two groups were compared in terms of the setup errors in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions. RESULTS: Compared with the control group, the test group showed a significantly shorter time for finishing the treatment (P<0.05) and a significantly lower proportion of children with treatment interruption (P<0.05). Compared with the control group, the test group showed smaller mean errors in the SI, LR and AP directions after image-guided radiotherapy, with significant differences in the mean errors in the SI and LR directions (P<0.05). CONCLUSIONS: With the application of the "kindergarten effect", most children can actively cooperate in radiotherapy, and it can also improve the accuracy and repeatability of positioning and help to achieve the desired treatment outcome.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

Challenges for the development of mutant isocitrate dehydrogenases 1 inhibitors to treat glioma.

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.

Natural products as potential lead compounds to develop new antiviral drugs over the past decade.

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.

Design and synthesis of selective FLT3 inhibitors via exploration of back pocket II.

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Random sperm DNA fragmentation index is not associated with clinical outcomes in day-3 frozen embryo transfer.

Damage to sperm DNA was proposed to play an important role in embryonic development. Previous studies focused on outcomes after fresh embryo transfer, whereas this study investigated the influence of sperm DNA fragmentation index (DFI) on laboratory and clinical outcomes after frozen embryo transfer (FET). This retrospective study examined 381 couples using cleavage-stage FET. Sperm used for intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) underwent density gradient centrifugation and swim up processing. Sperm DFI had a negative correlation with sperm motility (r = -0.640, P < 0.01), sperm concentration (r = -0.289, P < 0.01), and fertilization rate of IVF cycles (r = -0.247, P < 0.01). Sperm DFI examined before and after density gradient centrifugation/swim up processing was markedly decreased after processing (17.1% vs 2.4%, P < 0.01; 65 randomly picked couples). Sperm progressive motility was significantly reduced in high DFI group compared with low DFI group for both IVF and ICSI (IVF: 46.9% ± 12.4% vs 38.5% ± 12.6%, respectively; ICSI: 37.6% ± 14.1% vs 22.3% ± 17.8%, respectively; both P < 0.01). The fertilization rate was significantly lower in high ( ≥25%) DFI group compared with low (<25%) DFI group using IVF (73.3% ± 23.9% vs 53.2% ± 33.6%, respectively; P < 0.01) but was equivalent in high and low DFI groups using ICSI. Embryonic development and clinical outcomes after FET were equivalent for low and high DFI groups using ICSI or IVF. In this study, sperm DFI did not provide sufficient information regarding embryo development or clinical outcomes for infertile couples using FET.

Prevalence and inconformity of refractive errors and ocular biometry of 3573 medical university freshman students for 4 consecutive years.

AIM: To evaluate the prevalence of refractive errors and ocular biometry in 3573 freshman students at Tianjin Medical University for 4 consecutive years. METHODS: In this university-based, cross-sectional study, comprising 3573 students, visual acuity (VA), slit-lamp examination, non-cycloplegic auto-refraction, and ocular biometry were recorded. RESULTS: The prevalence of myopia increased annually, from 2017 to 2020 were 93.5%, 94.5%, 95.9%, and 96.2%, respectively (P=0.03), and the prevalence of high myopia was 25.7%, 26.9%, 28.6%, and 28.6%, respectively. Males tended to have a higher percentage of total astigmatism than females, with astigmatism ≥0.75 and ≥1.0 D criteria. The percentage of with-the-rule astigmatism, against-the-rule astigmatism, and oblique astigmatism was 90.3%, 5.8%, and 3.9%, respectively, with astigmatism ≥1.00 D criteria. The mean spherical equivalent, axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), corneal radius (CR), and lens position (LP) were 4.37±2.52 D, 25.28±1.24 mm, 539.49±34.98 µm, 3.31±0.34 mm, 3.47±0.21 mm, 7.8±0.28 mm, and 5.04±0.32 mm, respectively. With diopter increase in myopia, the AL became longer, CR became steeper, ACD became deeper, LT became thinner, and LP became more posterior (all P<0.01). Females had a shorter AL, thinner CCT, smaller CR, shallower ACD, thicker lens, and more anterior LP than males (P<0.01). The 64% of high myopia had AL≥26 mm, meanwhile, 5.8% mild myopia and 21.1% moderate myopia had AL≥26 mm. With AL≥26 mm, mild and moderate myopia compared to high myopia, AL was shorter (26.51±0.46 vs 26.87±0.70 mm), CR was larger (8.10±0.3 vs 7.85±0.23 mm) and LT was thinner (3.39±0.19 vs 3.45±0.19 mm, P<0.001). CONCLUSION: The prevalence of myopia and high myopia is significantly high in freshman students. The majority of astigmatism is with-the-rule. Inconformity of refractive errors and ocular biometry existed in some students. Attention should be paid to the ocular biometry of myopia.

[Effect of timing of acupuncture on limb dysfunction in patients with cerebral infarction: a multicenter prospective cohort pilot study].

OBJECTIVE: To evaluate the clinical efficacy of acupuncture at different timings in acute stage for limb dysfunction in patients with cerebral infarction. METHODS: A total of 101 patients with cerebral infarction limb dysfunction were divided into an early exposure group (n=51) and a late exposure group (n=50) according to the time of first acupuncture treatment during the acute phase. SPSS 25.0 software was used to balance the baseline between the two groups, and 31 pairs of matched patients were included, including 31 cases in the early exposure group and 31 cases in the late exposure group. The two groups were treated with Xingnao Kaiqiao acupuncture at Shuigou (GV 26), Neiguan (PC 6), Sanyinjiao (SP 6), Jiquan (HT 1), Chize (LU 5), Weizhong (BL 40), etc., once a day, and the course of treatment was not limited. In the early exposure group, acupuncture was started after 1 to 3 days of onset; in the late exposure group, acupuncture was started after 11 to 14 days of onset. The modified Rankin scale (mRS) grade was recorded before treatment, 30 and 60 days after onset; Fugl-Meyer assessment (FMA) grade was observed before treatment and 30 days after onset; the effect of acupuncture timing on the patients was analyzed by logistic analysis. RESULTS: Compared before treatment, the mRS grade at 30 and 60 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05); compared before treatment, the FMA grade at 30 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05). The timing of acupuncture was independently correlated with the disability status and the severity of motor dysfunction at 30 days after onset, and the disability status at 60 days after onset (P<0.05). Compared with the late exposure group, the possibility of becoming non-disabled at 30 days after onset (OR=22.882, 95%CI: 4.034-129.778), normal limb motor dysfunction (OR=22.320, 95%CI: 3.454-144.213) and non-disabled at 60 days after onset (OR=8.650, 95%CI: 2.437-30.696) in the early exposure group was increased. CONCLUSION: The timing of acupuncture is an independent factor affecting the disability status and limb motor dysfunction in patients with cerebral infarction, and the effect of early intervention may be better than late intervention.

[Exploration of indication of prophylactic transcatheter arterial chemoembolization on postoperative recurrence of hepatocellular carcinoma].

OBJECTIVE: To evaluate the efficacy of prophylactic transcatheter arterial chemoembolization (TACE) on postoperative recurrence of hepatocellular carcinoma. METHODS: A retrospective analysis was performed on clinicopathologic data of 260 hepatocellular carcinoma patients who underwent curative hepatectomy in Eastern Hepatobiliary Surgery Hospital, Second Military Medical University from January 2004 to June 2007. Among the 260 patients, 104 underwent postoperative prophylactic TACE and the other 156 were not. RESULTS: The overall survival rates at 1- and 2-years were 84.1% and 70.5% respectively. The overall disease-free survival rates at 1- and 2-years were 69.2% and 58.4% respectively. Of 260 overall patients, the disease-free survival rates at 1- and 2-years were 72.8% and 54.9% respectively in TACE group, and 66.9% and 59.7% respectively in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-years between TACE group and non-TACE group were not observed (P = 0.145, P = 0.405). Of 62 patients with tumor size >or= 10 cm, the disease-free survival rates at 1- and 2-years were respectively 66.6% and 48.7% in TACE group, and respectively 44.6% and 31.2% years between TACE group and non-TACE group were observed (P = 0.025, P = 0.025). Of 38 patients with vascular tumor thrombi, the disease-free survival rates at 1- and 2-years were respectively 33.0% and 0 in TACE group, and respectively 26.2% and 21.8% in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1-years between TACE group and non-TACE group was observed (P = 0.025), and not at 2-years (P = 0.122). CONCLUSIONS: In non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-Prophylactic TACE is preferred for hepatocellular carcinoma patients with high risk factors for recurrence such as tumor size >or= 10 cm and presented vascular tumor thrombi.

Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. METHODS: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. RESULTS: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-ß (PDGFR-ß), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. CONCLUSION: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

[Treatment strategy for synchronous liver metastasis from colorectal cancer].

BACKGROUND & OBJECTIVE: The patients with synchronous liver metastasis from colorectal cancer might get long-term survival after liver resection. But the optimal timing of surgery is undefined. This study was to explore the treatment strategy for synchronous liver metastasis from colorectal cancer. METHODS: From 1995 to 2005, 83 patients with synchronous liver metastasis from colorectal cancer were treated with operation at Eastern Hepatobiliary Surgery Hospital. Of the 83 patients, 37 received simultaneous liver and colorectal resection, and 46 received staged resection. The occurrence rate of postoperative complications, mortality, blood loss, hospital duration, overall survival rate, median survival time, disease-free survival time and recurrence rate of the 2 groups were compared. RESULTS: The occurrence rates of postoperative complications were 24.3% in simultaneous resection group and 19.6% in staged resection group (P=0.601). No operation-related death occurred. The mean blood losses were 462 mL in simultaneous resection group and 574 mL in staged resection group (P=0.312). The mean hospital duration was 19 days in simultaneous resection group and 36 days in staged resection group (P=0.001). The 1-, 3-and 5-year overall survival rates were 86.5%, 54.1%, and 27.0%, respectively, in simultaneous resection group and 89.1%, 52.2%, and 23.9%, respectively, in staged resection group (P>0.05). The median survival time was 40 months in simultaneous resection group and 37 months in staged resection group (P=0.075)û the median disease-free survival time was 12 and 11 months, respectively (P=0.532). The recurrence rates were 35.1% in simultaneous resection group and 30.4% in staged resection group (P=0.650). CONCLUSION: Synchronous liver and colorectal resection is preferred for synchronous liver metastasis from colorectal cancer.