Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Alzheimer's disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC₅₀s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3 × Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.
Animals ; Alzheimer Disease/genetics* ; Mice, Transgenic ; Glycogen Synthase Kinase 3 beta/metabolism* ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism* ; Cholinesterase Inhibitors/therapeutic use* ; Humans ; Autophagy/drug effects* ; Cognitive Dysfunction/pathology* ; Neuroprotective Agents/pharmacology*

Objective To explore the patterns of functional gait asymmetry during the support phase and the differentiation of bilateral foot functions,to gain insights into the human movement compensa-tion mechanisms and stability control characteristics,so as to provide theoretical references for the pre-vention and rehabilitation treatment of unilateral foot and ankle injuries.Methods Twelve young females with normal feet were recruited,and the time percentage of each phase of the support period,the change of longitudinal arch angle,the vertical ground reaction force and the center of plantar pressure trajectory of the dominant and non-dominant feet were collected by using a three-dimensional motion capture and a high-frequency plantar pressure testing system when the subjects walked at the optimum speed with the incremental loading of weights[0%body weight(BW),10%BW and 20%BW].The ef-fects of laterality(dominant foot,non-dominant foot)and load(0%BW,10%BW,20%BW)on arch changes and gait parameters,and the interactions between them,were analyzed using a two-way re-peated-measures ANOVA.Results The factors of laterality and load interacted significantly on arch changes,but not on gait parameters.(2)Compared with 0%BW,the time percentage of the buffering phase of the nondominant feet with the load of 20%BW increased(P<0.05),while that of the domi-nant ones decreased(P<0.05),with an increase in the buffering load of both feet with the load of 20%BW(P<0.05)and the buffering force excursion of both feet with the load of 10%BW(P<0.05).More-over,changes in longitudinal arch angle increased(P<0.05)with the load of 10%and 20%BW,the pedal extension load rate increased(P<0.05)with the above BW load in the non-dominant feet,and the horizontal slope of pedal extension decreased(P<0.05)with 20%BW load in the dominant feet.Compared with 10%BW,when the feed was loaded 20%BW,the time percentage in the buffering phase and the buffering force offset of the dominant feet decreased(P<0.05),while the buffering load of both feet increased(P<0.05).(3)Compared with the non-dominant feet,for the dominant feet,the buffering load rate at the load of 10%and 20%BW and changes in the longitudinal arch angle at the load of 20%BW decreased(P<0.05),while the horizontal slope of the pedal extension without load in-creased(P<0.05).Conclusion Walking with load induces function differentiation in bilateral feet.The dominant foot has more efficient horizontal extension without load and better buffering function in the vertical direction with loads,while the non-dominant feet perform a more adequate weight-bearing and extension function vertically with larger load.It is suggested that unilateral injury feet should not be given too much load,and it is inappropriate to select a single foot to represent and evaluate the func-tion and injury risk of the double feet in loaded walking.

Objective:To investigate the association between tumor necrosis factor-β (TNF-β) gene polymorphisms and genetic predisposition to gastric cancer, and to analyze the relationship between specific genotype of TNF-β and serum levels of TNF-β.Methods:Using case control study, we selected 153 patients with gastric cancer in Fudan University Shanghai Cancer Center between September 2021 and December 2022 as the gastric cancer group, and 150 healthy individuals were chosen as the healthy control group. In the previous study, 30 peripheral blood DNA samples of gastric cancer patients and healthy controls respectively were amplified by conventional PCR, which were sequenced to identify the genotype frequencies of TNF-β polymorphic loci (rs1041981, rs2229092, rs2229094 and rs78613290); consequently, Allele-Specific Quantitative PCR was used to further detect and analyze the genotype and genotype frequencies of TNF-β polymorphic loci; serum TNF-β levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA), and the relationship with specific genotypes of TNF-β was analyzed. Chi-square test and Fisher test were used to analyze the genotype distribution frequency of TNF-β polymorphic loci, and non-parametric statistics was used to analyze the differences in serum TNF-β expression levels.Results:The sequencing results showed that the genotype distribution of rs1041981 in gastric cancer group was CC 16.67% (5/30), CA 40.00% (12/30) and AA 43.33% (13/30). The genotype distribution in control group was CC 40.0% (12/30), CA 43.33% (13/30), AA 16.7% (5/30). The difference of genotype frequency between the two groups was statistically significant (χ 2=6.478, P=0.039). The genotypes of the polymorphic loci rs2229092 in both groups were AA, AG, and GG, with no statistically significant difference between the two groups (χ 2=1.888, P=0.612). The distribution frequencies of the genotypes of the polymorphic loci rs2229094 (TT and TC) and rs78613290 (GG and AG) showed no statistically significant differences between the two groups (both P>0.05). Further validation with an expanded clinical samples (153 cases in the gastric cancer group and 150 cases in the control group) found that the difference of rs1041981 genotype distribution between the gastric cancer group [CC 15.69%(24/153), CA 54.9%(84/153), AA 29.4%(45/153)] and the control group [CC 27.3%(41/150), CA 58.0%(87/150), AA 14.7%(22/150)] was significantly different (χ 2=12.366, P=0.002). Analysis of the influence of different allele frequencies on the risk of gastric cancer revealed that the odds ratio ( OR) of the A allele of rs1041981 for the risk of gastric cancer compared to the C allele was 1.701 (95% CI 1.235?2.355). Gene phenotype analysis combining the clinicopathological characteristics of gastric cancer patients found that the distribution frequency of the rs1041981 genotype was significantly different among groups of different genders, tumor invasion depths, and the lymph node metastasis, with statistically significant differences (All P>0.05). Additionally, gastric cancer patients with rs1041981 AA genotypes had higher serum TNF-β expression levels than those with CA and CC genotypes, (both P<0.05). Conclusions:The gene type frequency of the TNF-β gene polymorphic loci (rs1041981, C>A) exhibited significant differences between the gastric cancer group and the healthy control group. The presence of the A allele in rs1041981 site increased the susceptibility to gastric cancer, and patients with different gene types displayed vaning levels of serum TNF-β, among which AA genotype ranks the highest level.

Objective:To explore the clinical risk factors of post-transplantation diabetes mellitus (PTDM) and establish a risk prediction model in kidney recipients.Methods:The clinical data and postoperative bedside measurements of blood glucose (BG) were retrospectively reviewed for 305 renal transplant recipients at First Affiliated Hospital of Zhejiang University School of Medicine from October 2018 to August 2019.According to whether or not PTDM occurred, they were assigned into two groups of PTDM (n=34) and non-PTDM (n=271). Risk factors were screened through single/multi-factor Logistic regression and PTDM prediction model was established.Results:The incidence rate of PTDM was 11.15%(34/305). Logistic regression analysis indicated that deceased donor, age ≥40 years, female, pre-hemoglobin A1c (Pre-HbA1c) and postoperative bedside BG value ≥11.1 mmol/L were the correlated factors for the occurrence of PTDM.Among them, female ( OR=3.13, 95% CI: 1.28-7.61), Pre-HbA1c ( OR=2.05, 95% CI: 1.12-3.74) and BG ≥11.1 mmol/L at 4pm Day 2/3 post-operation ( OR=19.08, 95% CI: 4.34-83.87) were risk factors for the occurrence of PTDM, The area under the model curve was 0.86 (95% CI: 0.79-0.93) with a Jordan index of 0.65, a sensitivity of 82.8% and a specificity of 82.3%. Conclusions:Female, Pre-HbA1c and fasting BG at 4 pm Day 2/3 post-operation ≥ 11.1 mmol/L are risk factors for the occurrence of PTDM.The prediction model has a decent predictive value.It is conducive to early clinical interventions and lowering the incidence rate of PTDM.

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) featured by clonal proliferation of platelets, thrombosis and hemorrhage. Portal hypertension is a serious complication of ET associated with poor prognosis. We report a patient with ET complicated with acute upper gastrointestinal hemorrhage and intestinal perforation due to portal hypertension. She had an uneventful recovery after surgical and endoscopic treatment.

Fetal adenocarcinoma of the lung (FLAC) is an extremely rare subtype of lung cancer, accounting for only 0.1% to 0.5% of primary pulmonary malignancy. In 2011, international multidisciplinary classification of lung adenocarcinoma developed by the International Association for the Study of Lung Cancer (IALSC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) classified FLAC as a variant of invasive adenocarcinoma. FLAC has been further divided into low-grade fetal adenocarcinoma (L-FLAC) and high-grade fetal adenocarcinoma (H-FLAC) as these two categories exhibit different clinicopathological features and biological behaviors. Here we report a case of high-grade fetal adenocarcinoma and summarize clinicopathologic features of fetal lung adenocarcinoma.
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Adenocarcinoma of Lung ; diagnostic imaging ; pathology ; surgery ; Fetus ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prognosis ; Tomography, X-Ray Computed

Objective To analysis the occurrence status of breast disease in married women in Tangshan area,and to provide basis for early prevention of breast cancer in this region.Methods 773 married women in Tangshan area were given mammography examination.The tissue biopsy or surgical treatment was recommended for patients with above grade 3 of breast imaging reporting and data system (BI-RADS) classification to obtain pathological diagnosis.Results In 773 women,482 cases (62.35 ％) were diagnosed as BI-RADS grade 2 or below,256 cases (33.12 ％) were BI-RADS grade 3,33 cases (4.27 ％) were BI-RADS grade 4,2 cases (0.26 ％) were BI-RADS grade 5.The distribution of each BI-RADS grade among different age group was statistically significant (x2 =17.90,P ＜ 0.001),35 cases got pathological diagnosis by biopsy or surgical treatment,including 30 cases of mammary gland hyperplasia,3 cases of breast fibroadenoma,and 2 cases of breast cancer.Conclusion Women's mammography screening is important for the prevention and early detection of mammary gland diseases.

Objective To assess the efficacy and safety of oral fosfomycin trometamal in patients with lower urinary tract infections ( UTIs) caused by multi drug resistant ( MDR) bacteria in the clinical setting in China.Methods Multicenter study was conducted from January 2011 to December 2011 in 12 hospitals in China.Three hundred and fifty-six patients with non-fever lower UTls were treated by fosfomycin trometamal 3 g once daily.Three hundred and fifty cases with complete data were further evaluated .One hundred and twenty ( 34.3%) were male and 230 ( 65.7%) were female.The average age was ( 49.9 ± 16.6) years.Depending of the results of urine culture at the first visit ,142 patients with E.coli, Klebsiella pneumonia, proteus, Staphylococcus aureus, Staphylococcus epidermidis and entercocous were analyzed.The susceptibility of MDR bacteria to fosfomycin trometamol were calculated . The clinical efficacy , bacteriological efficacy of fosfomycin trometamol to these patients was evaluated .Results For the gram-negative bacteria detected by culture , among the E.coli, Klebsiella pneumonia and proteus, 50%(52/104) were Extended-Spectrum β-lactamases producing organisms . For the gram-positive bacteria ( n =38 ) detected by culture, methicillin-resistant staphylococcus accounts for 55%(11/20) of all the Staphylococcus and the other gram-positive bacteria were Enterococcus ( n=18 ) .Higher susceptibility rates to fosfomycin trometamol were observed among MDR bacteria (85.7%) and the clinical effective rate and bacteriological effective rate of fosfomycin trometamol were 96.4%( 53/55 ) and 87.5%( 42/48 ) , respectively .The incidence of drug-related adverse events (AEs) was 5.6%(20/356).The most common AE was diarrhea. No drug-related serious adverse events were found .Conclusions The distributions of uropathogens in China are complicated. The detection rate of MDR uropathogens is high . The dosing regimen of fosfomycin trometamal 3 g once daily is effective and tolerable for the patients with lower UTIs caused by MDR bacteria . It may represent good options for the empiric therapy for the patients with lower UTIs .

Objective To investigate the effects of different delivery way on long-term youth primipara urinary tract function. Methods All 175 cases of health primipara were collected from February 2008 to February 2009 in our hospi-tal, they were divided into two groups according to the difference delivery manner:the vaginal delivery group (n=95), the cesarean group (n=80), the lower urinary tract function of the primipara five years after the initial delivery of vagi-nal delivery and cesarean delivery mode were surveyed with ICIQ-FLUTS , the urinary flow rate were tested with La-borite Spindle View TM flow rate meter. Results ①The Qmax, average flow rate of the vaginal delivery group was higher than that of the cesarean group , up to the maximum flow rate was less than that of the cesarean group , but there were no significant difference between two groups (P>0.05). ②The urinary frequency, nocturia, stress inconti-nence incidence of the vaginal delivery group were lower than that of the cesarean section group , abdominal urination , intermittent urination, hesitancy, the mixed incontinence incidence were higher than that of the cesarean section group , but there were no significant difference between two groups ( P>0 . 05 ) . The urge incontinence incidence was lower than that of the cesarean section group , urgency incidence was higher , there was significant between two group (P<0.05).③The age and body mass index of the postpartum incontinence group was higher than that of the non-postpartum incontinence group, there was significant difference between two groups(P<0.05). Conclusion Vaginal de-livery and cesarean section two modes of production in early youth mothers have higher after five years incidence of lower urinary tract symptoms, age and body mass index factors of postpartum incontinence occurred.