Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objective:To investigate the transcriptional level expression of olfactomedin-like protein 2A (OLFML2A) in peripheral blood of patients with acute leukemia (AL) and its diagnostic and prognostic evaluation value.Methods:A retrospective cohort study was conducted. A total of 34 patients with AL (AL group) admitted to the Second People's Hospital of Lianyungang from January 2019 to March 2023 were selected, including 26 cases of acute myeloid leukemia (AML) (non-acute promyelocytic leukemia) and 8 cases of acute lymphoblastic leukemia (ALL). Another 15 healthy subjects who underwent the physical examination during the same period were selected as the healthy control group. Among 26 patients with AML, 18 were males and 8 were females. The median age [ M (IQR)] was 59 (9) years; 5 cases relapsed. Among 8 patients with ALL, 4 were males and 4 were females. The median age was 48 (12) years; 1 case relapsed. Real-time fluorescence quantitative polymerase chain reaction (qPCR) medthod was used to detect the relative expression level of OLFML2A mRNA in peripheral blood of each group. The relative expression levels of OLFML2A mRNA among the different patients stratified by clinicopathological factors were compared. Taking bone marrow smear cytology or bone marrow biopsy as the gold standard, receiver operating characteristic (ROC) curve was used to analyze the diagnostic effect of the relative expression level of OLFML2A mRNA on AML and ALL. According to the median relative expression level of OLFML2A mRNA in AL patients, the patients were divided into the high expression of OLFML2A mRNA (≥ the median) and the low expression of OLFML2A mRNA (< the median) groups. Progression-free survival (PFS) and overall survival (OS) of both groups were analyzed by using Kaplan-Meier curve. The log-rank test was used for comparison between groups. Results:The median relative expression level of OLFML2A mRNA in AL group was higher than that in the healthy control group [3.53 (8.19) vs. 0.27 (0.23)], and the difference was statistically significant ( Z = 4.38, P < 0.001). The median relative expression level of OLFML2A mRNA in AML group was higher than that in ALL group [4.92, (9.80) vs. 1.60 (4.35)], which were higher than that in the healthy control group; and the differences were statistically significant (all P < 0.05). There were statistically significant differences in the relative expression level of OLFML2A mRNA among AML patients with different prognosis risk stratification, fusion gene positive or not, whether there was chromosome abnormality, and whether the average daily hospitalization cost was < 2 500 yuan (all P < 0.05). There were statistically significant differences in the relative expression level of OLFML2A mRNA among ALL patients with different prognostic risk stratification, whether there was fusion gene and whether there was chromosome abnormality (all P < 0.05). ROC curve analysis showed that the area under the curve for the diagnosis of AML based on the relative expression level of OLFML2A mRNA was 0.936 (95% CI: 0.862-1.000), and the optimal cut-off value was 0.780; the area under the curve for the diagnosis ALL was 0.767 (95% CI: 0.535-0.998), and the optimal cut-off value was 0.558. Kaplan-Meier survival curve analysis showed that the 3-year PSF rate in AL patients with high expression of OLFML2A mRNA (17 cases) and low expression of OLFML2A mRNA was 20.5% and 30.6%, respectively, and PFS in AL patients with low expression of OLFML2A mRNA was superior to those with high expression, and the difference was statistically significant ( χ2 = 4.64, P = 0.031). The 3-year OS rates in AL patients with high and low expression of OLFML2A mRNA was 40.4% and 33.3%, respectively, and there was no statistically significant difference in OS between the 2 groups ( χ2 = 1.55, P = 0.213). Conclusions:The relative expression level of OLFML2A mRNA is high in AL patients, and it is more significant in AML patients. The level of OLFML2A gene has a certain value in the diagnostic and prognostic evaluation of AL.

Objective:To explore the relationship between Epstein-Barr virus (EBV) infection, hepatitis B virus (HBV) reactivation and clinical features and prognosis in HBV-infected non-Hodgkin lymphoma (NHL) patients and influencing factors of HBV reactivation.Methods:A retrospective cohort study was conducted. A total of 80 NHL patients with hepatitis B surface antigen (HBsAg) positive (which was defined as HBV positive) who were admitted to the Second People's Hospital of Lianyungang and Jiangsu Province Hospital from December 2012 to October 2022 were selected. All patients were divided into EBV-positive group and EBV-negative group according to EBV DNA results, and further grouped into the HBV reactivation group and the non-reactivation group according to whether HBV were reactivated after chemotherapy. The clinical characteristics of patients among groups were compared. Multivariate logistic regression model was used to analyze the factors influencing HBV reactivation. The Kaplan-Meier method was used to evaluate the progression-free survival (PFS) and overall survival (OS) of patients, and the log-rank test was used for inter-group comparison.Results:Among NHL patients with HBV positive, 27 cases (33.8%) were EBV-positive and 29 cases (36.3%) were HBV reactivation. Compared with the EBV-negative group, the proportion of patients with Ann Arbor stage Ⅲ-Ⅳ [92.6% (25/27) vs. 66.0% (35/53)], elevated β 2-microglobulin level [88.9% (24/27) vs. 62.3% (33/53)], bone marrow involvement [40.7% (11/27) vs. 15.1% (8/53)], and HBV reactivation [51.9% (14/27) vs. 28.3% (15/53)] was higher in the EBV-positive group, and the differences were statistically significant (all P<0.05). There were no statistically significant differences in the composition of patients stratified by age, gender, pathological type, B symptom, lactate dehydrogenase level, international prognostic index score, number of extranodal involvements, liver involvement, hepatitis outbreak, prophylactic anti-HBV therapy, hepatitis B surface antibody (HBsAb), rituximab therapy, and the last chemotherapy effects between the 2 groups (all P > 0.05). Compared with the HBV non-reactivation group, the proportion of patients undergoing hepatitis outbreak [48.3% (14/29) vs. 17.6% (9/51)], not receiving prophylactic anti-HBV therapy [65.5% (19/29) vs. 39.2% (20/51)], HBsAb negative [79.3% (23/29) vs. 21.6% (11/51)], EBV positive [48.3% (14/29) vs. 25.5% (13/51)], receiving rituximab [82.8% (24/29) vs. 60.8% (31/51)] was higher in the HBV reactivation group, and the differenves were statistically significant (all P < 0.05); while there were no statistically significant differences in the composition of patients stratified by the other clinical characteristics between the 2 groups (all P > 0.05). Multivariate logistic regression analysis showed that EBV-positivity was an independent risk factor for HBV reactivation after chemotherapy in NHL patients with HBsAg positive ( OR = 7.073, 95% CI: 1.613-31.010, P = 0.009), while HBsAb positive ( OR = 0.038, 95% CI: 0.008-0.186, P < 0.001) and preventive anti-HBV therapy ( OR = 0.172, 95% CI: 0.039-0.756, P = 0.020) were independent protective factors. The last follow-up was in December 2023 and the median follow-up time was 36.5 months. There were no statistically significant differences in PFS and OS between the EBV-positive group and the EBV-negative group, HBV reactivation group and the non-reactivation group (all P > 0.05). Conclusions:Among HBV-infected NHL patients, those with concurrent EBV infection have a more advanced clinical stage and are very prone to bone marrow invasion, and they also show a higher probability of HBV reactivation; HBV reactivation may be related to whether receiving preventive anti-HBV therapy and rituximab therapy. EBV infection may increase the risk of HBV reactivation in NHL patients; EBV infection and HBV reactivation may not be relevant to the prognosis of patients.

Acute T-lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy, and in recent years, with the advancement of combined chemotherapy and hematopoietic stem cell transplantation, the prognosis of T-ALL has improved significantly, but for patients with primary drug resistance or relapsed/refractory disease the prognosis is still poor. The plant homeodomain finger 6 (PHF6) is a tumor suppressor protein, it plays a pivotal role in T cell differentiation, epigenetic regulation and oncogenic pathway synergy, and its mutations and deletions are commonly associated with the development of T-lymphocytic leukemia. However, the underlying mechanism of PHF6 in the pathogenesis of T-ALL remains unclear. This article reviews the structure, function and mechanism of action of PHF6 in T-ALL, the important coexisting genes associated with the progression of T-ALL, and the research progress in targeted therapy.

Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolu-tionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase Ⅲ clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by estab-lishing a physiologically based pharmacokinetics(PBPK)model.For in vitro-in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objective:To investigate the factors influencing the right heart dysfunction in myloproliferative neoplasm (MPN) patients with BCR::ABL fusion gene-negative.Methods:A retrospective case-control study was conducted. A total of 130 MPN patients with BCR::ABL fusion gene-negative admitted to the Second People's Hospital of Lianyungang from January 2020 to December 2022 were selected as the study objects. The general data, laboratory indexes and cardiac function parameters were collected. All patients were divided into the control group (non-right heart function injury, 96 cases) and the observation group (right heart function injury, 34 cases) according to whether there was right heart dysfunction judged by ultrasonic cardiogram. Multivariate logistic regression analysis was used to analyze the independent influencing factors of right heart dysfunction in MPN patients with BCR:: ABL fusion gene-negative. Taking right heart dysfunction judged by ultrasonic cardiogram as the gold standard, the receiver operating characteristic (ROC) curve was drawn to predict right heart dysfunction according to independent influencing factors, and the diagnostic efficacy of the factors was analyzed.Results:The median age was 57 years old (range 19-76 years); among the 130 patients, 62 cases were male and 68 cases were female. There were 69 cases of primary thrombocytosis, 35 cases of polycythemia vera and 26 cases of primary myelofibrosis. The proportions of patients with age > 60 years old, hypertension, embolism history, pulmonary hypertension in the observation group were higher than those in the control group, and the differences were statistically significant (all P < 0.05). There were no statistically significant differences in the composition of patients with gender, body mass index > 28 kg/m2, smoking, drinking, diabetes, hyperlipidemia and different pathological types between the two groups (all P > 0.05). The white blood cell count, neutrophil count, basophil count, monocyte count, red blood cell count, hematocrit (Hct), CD34+ cell count and platelet count in the observation group were higher than those in the control group, and the differences were statistically significant (all P < 0.05). There were no statistically significant differences in lymphocyte count, eosinophilic count, triglyceride, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and high sensitive C-reactive protein levels between the two groups (all P > 0.05). The cardiac ejection time in the observation group was shorter than that in the control group, but the transverse diameter of right atrium, anteroposterior diameter of right ventricle, anterior wall thickness of right ventricle, isovolumic systole time, isovolumic diastole time and right ventricular Tei index in the observation group were all higher than those in the control group, and the differences were statistically significant (all P < 0.001). Multivariate logistic regression analysis showed that age > 60 years (OR = 1.520, 95% CI: 1.250-1.692, P = 0.002), embolism history (OR = 1.765, 95% CI: 1.302-2.020, P = 0.001), pulmonary arterial hypertension (OR = 1.555, 95% CI: 1.303-1.702, P = 0.001), elevated Hct (OR = 1.900, 95% CI: 1.587-2.269, P = 0.002), the increased density of CD34+ cell (OR = 1.400, 95% CI: 1.158-1.630, P = 0.001), and increased Tei index of right ventricle (OR = 2.269, 95% CI: 1.700-3.568, P = 0.001) were independent risk factors of right heart dysfunction in MPN patients with BCR::ABL fusion gene-negative. ROC curve analysis showed that the area under the curve of age > 60 years old, embolism history, pulmonary arterial hypertension, Hct, the density of CD34+ cell, and Tei index of right ventricle, in predicting right heart dysfunction in MPN patients with BCR-ABL fusion gene-negative was 0.780 (95% CI: 0.690-0.925), 0.657 (95% CI: 0.533-0.740), 0.728 (95% CI: 0.660-0.813), 0.619 (95% CI: 0.510-0.708), 0.777 (95% CI: 0.720-0.809), 0.822 (95% CI: 0.749-0.886), respectively. The area under the curve of the 6 combined items was 0.930 (95% CI: 0.850-0.987). The sensitivity and specificity were 89.69% and 96.38% respectively when the optimum critical value was reached.Conclusions:Age > 60 years old, embolism history, pulmonary arterial hypertension, elevated Hct, the increased density of CD34+ cell and increased Tei index of right ventricle are independent risk factors of right heart dysfunction in MPN patients with BCR::ABL fusion gene-negative.

Objective:To study and screen the differential expression of inflammatory proteins in diabetes skin ulcers and common skin ulcers, so as to provide experimental basis for further research on anti-inflammatory and healing drug targets of diabetes skin ulcers.Methods:The tissues of 11 patients with diabetes skin ulcer, 12 patients with common skin ulcer and 11 patients with normal skin were collected from the First Hospital of Hunan University of Chinese Medicine. The levels of inflammatory protein Toll like receptor 4 (TLR4), nuclear factor κB (NF-κB), pro-inflammatory factor interferon -γ (IFN -γ), tumor necrosis factor - α (TNF -α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1β (IL-1β), macrophage chemotactic protein-1 (MCP-1), anti-inflammatory factors epidermal growth factor (EGF), interleukin-4 (IL-4), and interleukin-10 (IL-10) were detected in three groups of tissues using enzyme-linked immunosorbent assay (ELISA).Results:Compared with normal tissues, the concentrations of TLR4, NF-κB, IFN -γ, TNF -α, IL-1β, IL-6, IL-8, MCP-1 and EGF in common ulcer skin tissues and diabetes ulcer tissues were higher, and the concentrations of IL-10 were lower, with statistically significant differences (all P<0.05); Compared with the normal tissue, the concentration of IL-4 in diabetes ulcer tissue was lower, the difference was statistically significant ( P<0.05); Compared with ordinary ulcer skin tissue, the concentrations of TLR4, NF-κB and MCP-1 in diabetes ulcer tissue were higher, and the concentrations of IL-4 were lower, with statistically significant differences (all P<0.05). Conclusions:The skin ulcer in diabetes patients will have inflammatory reaction, and high glucose promotes the inflammatory reaction of skin ulcer, which may be related to the abnormal expression of TLR4, NF-κB, MCP-1 and IL-4. TLR4/NF-κB signal pathway and inflammatory factors MCP-1 and IL-4 may be the target of the inflammation regulation of diabetes skin ulcer.

Objective:To investigate the therapeutic effect and safety of pomadomide combined with cyclophosphamide and dexamethasone (PCD) in the treatment of relapsed/refractory multiple myeloma (MM).Methods:The clinical data of 20 relapsed/refractory MM patients receiving PCD regimen in the Second People's Hospital of Lianyungang Affiliated to Bengbu Medical College from March 2021 to June 2022 were retrospectively analyzed; and 29 relapsed/refractory MM patients receiving other regimens including DECP (dexamethasone+etoposide+cyclophosphamide+cisplatin, 13 cases) and VCD (bortezomib+ cyclophosphamide+ dexamethasone, 16 cases) during the same period were treated as the control group. The efficacy and adverse effects of both groups were compared after 4 cycles of treatment.Results:After 4 cycles of treatment, the overall response rate (ORR) and the clinical benefit rate (CBR) of 20 cases in PCD group was 70.0% (14/20) and 85.0% (17/20), respectively; among 20 cases, there were 5 cases of complete response (CR), 4 cases of very good partial remission (VGPR), 5 cases of partial remission (PR), 3 cases of minimal remission (MR), 2 cases of stable disease (SD), 1 case of the progression of the disease (PD). ORR and CBR of 29 cases in the control group was 41.4% (12/29) and 65.5% (19/29), respectively; among 29 cases, there were 2 cases of CR, 3 cases of VGPR, 7 cases of PR, 7 cases of MR, 5 cases of SD, 5 cases of PD. There was a statistically significant difference in ORR of both group ( χ2 = 3.89, P = 0.048), while the difference in CBR of both group was not statistically significant ( χ2 = 2.30, P = 0.129). There were 2 patients with renal impairment achieving CR in PCD group and 1 patient with renal impairment achieving CR in the control group ( P = 0.152); 1 genetically high-risk patient achieved CR in PCD group and none of patients in the control group achieved CR, and the difference was statistically significant ( P>0.05). The common hematological adverse effects of two groups were anemia, neutropenia, thrombocytopenia; the common non-hematological adverse effects were malaise, infection and fatigue, and the differences were statistically significant (all P>0.05). The incidence of grade 3-4 infection was 25.0% (5/20) in PCD group and the disease was under the control after anti-infective therapy, and the incidence of grade 3-4 infection was 24.1% (7/29) in the control group; and the difference was not statistically significant ( P > 0.05). Conclusions:PCD regimen has good clinical efficacy and safety in treatment of relapsed/refractory MM.

Objective:To investigate the clinical significances of evaluation indexes of right heart function injury in patients with BCR-ABL-negative myroproliferative neoplasms (MPN).Methods:The clinical data of 208 patients with BCR-ABL-negative MPN diagnosed in the Second People's Hospital of Lianyungang and Jiangsu Province Hospital from January 2015 to August 2021 were retrospectively analyzed, including 63 cases of primary myelopathic fibrosis (PMF), 39 cases of polycytosis vera (PV) and 106 cases of essential thrombocythemia (ET). The clinical characteristics of patients and the examination results of hematological related indicators were compared among the three groups. The examination results of indexes of right heart function injury were analyzed, including echocardiography, brain natriuretic peptide, soluble growth stimulation expression gene-2 (sST-2), lactate dehydrogenase (LDH), D-dimer, ferritin, β 2-microglobulin, peripheral blood WT1 gene, CD34 + cell count, etc. Results:Of the 208 patients, 109 were male and 99 were female; the median age was 62 years old (23 years old, 89 years old). The differences in levels of hemoglobin, platelet count, D-dimer, LDH and ferritin among PMF, PV and ET patients were statistically significant (all P < 0.05). Color echocardiography was performed in 87 patients, including 26 cases of PMF, 19 cases of PV and 42 cases of ET. Pulmonary artery pressure increased in 69 cases (79.3%), left atrial diameter increased in 76 cases (87.3%), and diameter increased during right ventricular diastolic period in 59 cases (67.8%). There were significant differences in pulmonary artery pressure, left atrial diameter and diameter during right ventricular diastolic period among PMF, PV and ET patients (all P < 0.05). Pearson correlation analysis showed that pulmonary artery pressure was positively correlated with ferritin, LDH, sST-2 and age ( r values were 0.796, 0.768, 0.915 and 0.734, all P<0.05), while it was negatively correlated with platelet count ( r = -2.330, P = 0.034). Conclusions:For BCR-ABL-negative MPN patients, the increase of pulmonary artery pressure, ferritin and LDH and the decreased platelet count and hemoglobin may increase the probability of right heart function impairment. For BCR-ABL-negative MPN patients with the higher levels of ferritin, LDH, sST-2, age, and the lower level of platelet count, the pulmonary artery pressure may be higher.

Objective:To investigate the knowledge, attitude and practice status of ophthalmic nurses on prevention and control of intraocular infection in grade Ⅲ class A hospitals.Methods:A self-made questionnaire was used to investigate the knowledge, attitude and practice of 236 nurses on prevention and control of intraocular infection in the ophthalmology department of 8 grade Ⅲ class A hospitals in Zhengzhou from January to June 2020. The correlation between the knowledge, attitude and practice were analyzed by Pearson correlation analysis and the influencing factors of each term were analyzed by multivariate Logistic regression.Results:The scores of knowledge, attitude, practice of all nurses were (26.08 ± 2.46), (67.45 ± 8.48), (50.31 ± 6.67) points, and the scoring rate were (87.0 ± 8.2)%, (84.3 ± 10.1)%, (83.9 ± 9.8)%, respectively. The scores of each dimension of knowledge, attitude and practice were significantly positively correlated ( r values were 0.26-0.42, all P<0.05), respectively. Multivariate Logistic regression analysis showed that education background, professional title and training experience of infection were the influencing factors of knowledge score ( P<0.05), education background, professional title, training experience of infection and demand were the influencing factors of attitude score ( P<0.05), and nursing age and work post were the influencing factors of practice score ( P<0.05). Conclusions:The level of knowledge, attitude and practice of ophthalmic nurses in grade Ⅲ class A hospitals on prevention and control of intraocular infection is overall good. Hospital management department still needs to make reasonable management countermeasures according to personnel characteristics to improve the knowledge, attitude and practice level of ophthalmic nurses and to reduce post-operative intraocular infection.