The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.
Humans ; Drug Resistance, Neoplasm/drug effects* ; Proto-Oncogene Proteins p21(ras)/metabolism* ; Mutation/genetics* ; Neoplasms/genetics* ; Antineoplastic Agents/therapeutic use*

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

UNLABELLED: OBJECTIVE：To explore the clinical characteristics and genetic etiology of a child with CAKUTHED syndrome. METHODS: A child who was admitted to the neonatal department of Gansu Provincial Maternal and Child Health Care Hospital due to "neonatal asphyxia" in May 2021 was selected as the study subject. Genomic DNA was extracted from peripheral venous blood samples from the child and his parents, and whole exome sequencing (WES) was carried out. Sanger sequencing was used to verify the candidate variant of the PBX1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital [Ethics No.: 2021GSFY (65)]. RESULTS: The proband, a male neonate, manifested renal dysplasia, congenital heart disease, pulmonary dysplasia, mediastinal hernia, cryptorchidism, and clavicle dysplasia. WES revealed that he had harbored a heterozygous c.863G>A (p.Arg288Gln) missense variant in exon 6 of PBX1 gene, which resulted substitution of Arginine at position 288 by Glutamine, for which both parents were of the wild type. The variant was unreported previously and rated as pathogenic (PS2+PM1+PM2_Supporting+PP2+PP3) based on the ACMG guidelines. CONCLUSION The c.863G>A variant of the PBX1 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PBX1 gene.
Humans ; Male ; Pre-B-Cell Leukemia Transcription Factor 1/genetics* ; Phenotype ; Infant, Newborn ; Exome Sequencing ; Mutation, Missense ; Heart Defects, Congenital/genetics* ; Abnormalities, Multiple/genetics*

BACKGROUND:Photothermal therapy is a novel tumor treatment strategy that uses photothermal agents to transform light energy into heat energy to accomplish non-invasive tumor ablation.The rise of photothermal therapy and nanotechnology has provided a new perspective on breast cancer treatment.OBJECTIVE:To prepare a new type of near-infrared biomimetic nanoprobe that has been modified by breast cancer cell membrane,to investigate the effect of near-infrared fluorescence/ultrasound imaging in vitro,and to observe its targeting ability and photothermal therapy effect on homologous tumor cells in vitro.METHODS:Organic small molecule ITIC-4CI with A-D-A structure was used as photothermal agents;polylactic acid/glycolic acid copolymer as nanocarrier;4T1 cell membrane of mouse breast cancer cells as a surface modifier of nanoparticles;perfluorohexane(PFH)was loaded.A novel near-infrared biomimetic nanoprobe(4T1m/ITIC-4CI/PFH)was prepared by the double emulsion evaporation method and sonication method.The basic characterization of the nanoprobe and the homologous targeting ability were detected.The photothermal properties and photothermal stability of the probe were investigated,and the near-infrared fluorescence/ultrasound imaging effect of the probe under laser irradiation was observed.The CCK-8 assay and calcein/propidium iodide staining were used to assess the efficacy of photothermal therapy.RESULTS AND CONCLUSION:(1)The prepared 4T1m/ITIC-4CI/PFH nanoprobes had uniform size,high stability,and an average particle size of(92.7±2.3)nm.The probe's protein composition was identical to that of the 4T1 cell membrane.The nanoprobe's ability to target homologous 4T1 cells was validated by an in vitro cell uptake assay.(2)The nanoprobe had a red-shift absorption spectrum and tail emission extending to the near-infrared-Ⅱ,which emitted a bright near-infrared-Ⅱ fluorescence signal under laser irradiation.(3)After laser irradiation,the nanoprobe 4T1m/ITIC-4CI/PFH could be turned into microbubbles and enhanced ultrasound imaging.The results of CCK-8 assay and calcein/propidium iodide staining showed that the nanoprobe 4T1m/ITIC-4CI/PFH had an obvious photothermal killing effect on 4T1 cells.(4)The results show that the nanoprobe 4T1m/ITIC-4CI/PFH has the ability to target homologous tumors and enhance near-infrared-Ⅱ fluorescence imaging/ultrasound imaging and photothermal therapy effects.

Objective:To explore the genetic basis for a patient with autosomal dominant retinitis pigmentosa (RP).Methods:A male patient with RP treated at Gansu Provincial Maternal and Child Health Care Hospital in September 2019 was selected as the study subject. Clinical data was collected. Peripheral blood samples of the patient and his parents were subjected to whole exome sequencing (WES). Candidate variant was validated by Sanger sequencing and bioinformatic analysis.Results:The patient, a 29-year-old male, developed night blindness, amblyopia, visual field defects and optic disc abnormalities since childhood. Gene sequencing revealed that he has harbored a heterozygous c. 942G>C (p.Lys314Asn) variant of the IMPDH1 gene, which was inherited from his mother, whilst his father was of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 942G>C variant was predicted as likely pathogenic (PM1+ PM2_Supporting+ PP3+ PP1). Conclusion:The c. 942G>C (p.Lys314Asn) variant in the IMPDH1 gene probably underlay the RP in this patient.

Objective:To discuss the effect of azathioprine(AZA)on ferroptosis in spermatocytes of the mice induced by reduced glutathione(GSH)peroxidase 4 inhibitor RSL3,and to clarify the potential mechanism.Methods:The spermatogonia GC-2 cells of the mice were randomly divided into control group(no treatment),RSL3 group(treated with 10 nmol·L-1 RSL3 for 24 h),RSL3+ferroptosis inhibitor(Ferrostatin-1,Fer-1)group(treated with 10 nmol·L-1 RSL3 for 24 h+2 μmol·L-1 Fer-1 for 12 h),RSL3+low dose of AZA group(treated with 10 nmol·L-1 RSL3 for 24 h+5 μmol·L-1 AZA for 12 h),RSL3+medium dose of AZA group(treated with 10 nmol·L-1 RSL3 for 24 h+10 μmol·L-1 AZA for 12 h),and RSL3+high dose of AZA group(treated with 10 nmol L-1 RSL3 for 24 h+20 μmol·L-1 AZA for 12 h).The MTT method was used to detect the activities of the GC-2 cells in various groups after treated with different concentrations of AZA and RSL3;the GSH and GSSG levels in the GC-2 cells were detected by GSH and oxidized glutathione(GSSG)detection kits;the malondialdehyde(MDA)levels in the GC-2 cells in various groups were detected by MDA detection kit;Western blotting method was used to detect the expression levels of long-chain acyl-CoA synthetase 4(ACSL4),heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4)proteins in the cells in various groups;immunofluorescence staining was used to detect the expressions of ACSL4 protein in the cells in various groups.Results:Compared with control group,the differences in activities of the GC-2 cells in 5,10,and 20 μmol·L-1 AZA groups had no significant differences(P＞0.05),while the activities of the GC-2 cells in 30 and 40 μmol·L-1 AZA groups were significantly decreased(P＜0.01);therefore,the AZA concentration was selected to be within 20 μmol·L-1.Compared with control group,the differences of the activities of the GC-2 cells in 1,5,and 10 nmol·L-1 RSL3 groups had no significant differences(P＞0.05),while the activities of the GC-2 cells in 50,100,500,and 1 000 nmol·L-1 RSL3 groups were significantly decreased(P＜0.05 or P＜0.01);therefore,the RSL3 concentration was set to be within 10 nmol·L-1.The GSH and MDA detection kits results showed that compared with control group,the levels of GSSG and MDA in the GC-2 cells in RSL3 group were significantly increased(P＜0.05),while the GSH levels were significantly decreased(P＜0.05);compared with RSL3 group,the levels of GSSG and MDA in the GC-2 cells in RSL3+Fer-1 group and RSL3+AZA group were significantly decreased(P＜0.01),while the GSH levels were significantly increased(P＜0.01).The Western blotting results showed that compared with control group,the expression levels of ACSL4 and HO-1 proteins in the GC-2 cells in RSL3 group were significantly increased(P＜0.05),while the expression level of GPX4 protein was significantly decreased(P＜0.01);compared with RSL3 group,the expression levels of GPX4 protein in the GC-2 cells in RSL3+Fer-1 group and RSL3+AZA group were significantly increased(P＜0.05),while the expression levels of ACSL4 and HO-1 proteins were significantly decreased(P＜0.01).The immunofluorescence staining results showed that compared with control group,the expression amount of ACSL4 protein in the GC-2 cells in RSL3 group was significantly increased,and compared with RSL3 group,the expression amounts of ACSL4 protein in the cells in RSL3+Fer-1 group and RSL3+AZA group were significantly decreased.Conclusion:AZA can alleviate the ferroptosis-induced by RSL3 in spermatocytes of the mice.

Objective Sepsis-induced acute respiratory distress syndrome(ARDS)is an independent risk factor for mortality in critically ill septic patients.However,effective therapeutic targets are still unavailable due to the lack of understanding of its unclear pathogenesis.With increasing understanding in the roles of circulating histones and endothelial dysfunction in sepsis,we aimed to investigate the mechanism of histone-induced endothelial dysfunction leading to sepsis-induced ARDS and to provide experimental support for histone-targeted treatment of sepsis-induced ARDS.Methods First of all,in vitro experiments were conducted.Human umbilical vein endothelial cells(HUVEC)were stimulated with gradient concentrations of histones to explore for the optimal stimulation concentration in vitro.Then,HUVEC were exposed to histones at an optimal concentration with or without resatorvid(TAK-242),a selective inhibitor of Toll-like receptor 4(TLR4),for 24 hours for modeling.The cells were divided into 4 groups:1)the blank control group,2)the blank control+TAK-242 intervention group,3)the histone stimulation group,and 4)the histone+TAK-242 intervention group.HUVEC apoptosis was determined by flow cytometry,VE-Cadherin expression in endothelial cells was determined by Western blot,and the integrity of adhesion connections between endothelial cells was evaluated with confocal fluorescence microscopic images.Male C57BL/6 mice aged 6-8 weeks and weighing 22-25 g were used for the in vivo experiment.Then,the mice were given cecal ligation and puncture(CLP)as well as histone injection at 50 mg/kg via the tail vein for sepsis modeling.The experimental animals were divided into 6 groups:1)the blank control group,2)the blank control+TAK-242 intervention group,3)the CLP model group,4)the CLP+TAK-242 intervention group,5)the histone model group,and 6)the histone+TAK-242 intervention group.After 24 h,the concentrations of serum interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)were determined using ELISA kits.Western blot was performed to determine the expression of vascular endothelial(VE)-cadherin in the lung tissue.Hematoxylin and eosin(HE)staining was performed to observe the pathological changes in the lung tissue of the mice.Evans Blue was injected via the tail vein 30 min before the mice were sacrificed.Lung tissue was collected after the mice were sacrificed.Then,the concentrations of Evans blue dye per unit mass in the lung tissue from mice of different groups were evaluated,the rates of pulmonary endothelial leakage were calculated,and the integrity of the pulmonary endothelial barrier was evaluated.Results The results of the in vitro experiment showed that,compared with those of the control group,HUVEC apoptosis was significantly increased under histone stimulation(P＜0.05),the expression of VE-cadherin was decreased(P＜0.05),and the integrity of adherens junctions between endothelial cells was damaged.TAK-242 can significantly inhibit histone-induced HUVEC apoptosis and VE-cadherin expression reduction and maintain the integrity of adherens junctions between endothelial cells.According to the findings from the in vivo experiments,in mice with CLP-induced and histone-induced sepsis,TAK-242 effectively alleviated the increase in serum concentrations of IL-6 and TNF-α,reduced the downregulation of VE-cadherin expression in the lung tissue(P＜0.05),decreased endothelial permeability of the lung vessels,and improved pathological injury in the lung tissue.Conclusion By binding to TLR-4,histone decreases VE-cadherin expression on the surface of vascular endothelial cells,disrupts the integrity of intercellular adherens junctions,and triggers pathological damage to lung tissue.Using TLR-4 inhibitors can prevent sepsis-induced ARDS in histone-induced sepsis.

Uremic pruritus,a severe complication in patients with chronic kidney disease,is associated with a high prevalence.It can cause depression and sleep disorders,and seriously affect the quality of life and the social relations of patients.Recently,there is growing evidence showing that κ-opioid receptor agonists,including nalfurafine,difelikefalin,and nalbuphine,can effectively and safely reduce itching symptoms in patients with refractory uremic pruritus.Herein,we reviewed the epidemiology,pathogenesis,clinical symptoms,and treatment strategies of uremic pruritus,and summarized in detail the progress in clinical research on the use of κ-opioid receptor agonists,including nalfurafine,difelikefalin,and nalbuphine,in the management of patients with uremic pruritus.

Objective:To understand the current status of the compliance of immunosuppressive drugs in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to explore the influencing factors of their compliance.Methods:This study was a cross-sectional study. Using the convenient sampling method, a total of 238 allo-HSCT patients who were followed up in the Transplant Center of Taizhou Hospital of Zhejiang Province, Zhejiang Provincial Hospital of Traditional Chinese Medicine and the First Affiliated Hospital of Wenzhou Medical University from March 2020 to February 2021 were selected as the research objects. The self-designed general information questionnaire, Basel Assessment Scale for Immunosuppressive Drug Compliance, Chinese version of Medication Belief-Specific Scale, General Self-Efficacy Scale, Perceived Social Support Scale and Family Care Index Scale were used for on-site investigation of patients. Pearson correlation analysis was used to analyze the correlation between medication compliance and medication belief, self-efficacy, social support and family care of allo-HSCT patients. Multiple linear regression analysis was used to investigate the influencing factors of immunosuppressive medication compliance in allo-HSCT patients.Results:A total of 238 questionnaires were distributed in this study, and 228 valid questionnaires were finally recovered. The medication compliance score of allo-HSCT patients was (4.80±1.18) points. And 111 patients (48.68%, 111/228) had poor medication compliance, among which the incidence of not taking medication on time was the highest, accounting for 44.30% (101/238) . Multiple linear regression analysis showed that average monthly family income, rejection, medication belief, social support and family care were the influencing factors of medication compliance ( P< 0.05) . Conclusions:The immunosuppressant medication compliance of allo-HSCT patients is at a medium and low level. Average monthly family income, rejection reaction, medication belief, social support and family care are the main factors affecting the immunosuppressant medication compliance of allo-HSCT patients. Medical staff should formulate targeted intervention measures according to the influencing factors of medication compliance to improve the immunosuppressive medication compliance of allo-HSCT patients.

Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.