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Reduced feed intake in early lactation prompts increased fat mobilization to meet dairy cow energy needs for milk production. The increased lipolysis in cows presents significant health risks with unclear mechanisms. The objectives of our study were to compare the longitudinal profiles of metabolites and lipids of serum from high- and low-lipolysis cows. Forty multiparous Holstein dairy cows were enrolled in the retrospective study. Serum samples were collected on d 7 before expected calving, as well as on d 5, 7, 14, and 21 postpartum. Dairy cows were grouped according to mean serum nonesterified fatty acids on d 5 and 7 after parturition as low (<0.600 mmol/L; n = 8; LFM) and high (>0.750 mmol/L; n = 8; HFM), indicating fat mobilization during early lactation. Lactational performance and serum metabolic parameters related to glucose and lipid metabolism, liver functions, oxidative status, and inflammatory responses were determined. Serum samples were subjected to liquid chromatography-MS-based metabolomics and lipidomics. Despite differences in postpartum BW change, there were no observed variations in milk yield and composition between the 2 groups. Serum ß-hydroxybutyric acid, glucose, leptin, aspartate aminotransferase, IL-6, and tumor necrosis factor alpha were greater in cows with HFM than in cows with LFM. Serum adiponectin, revised quantitative insulin sensitivity check index, and albumin were lower in cows with HFM than in cows with LFM. Intensified fat mobilization in the HFM cows came along with reduced estimated insulin sensitivity, impaired liver functions, and increased oxidative stress and inflammatory responses. Differences in metabolic patterns were observed across the transition period when comparing serum blood matrixes (e.g., in different amino acids, acylcarnitines, and sphingolipids). The serum metabolome of the HFM cows was characterized by higher concentrations of glycine, acylcarnitines, carnosine, Cer(d20:0/18:0), Cer(d18:1/16:0), and Cer(t18:0/24:0) compared with LFM cows. The differential serum metabolites and lipids at different sampling times during the peripartum period were enriched in the sphingolipid metabolism. Differences in serum metabolic status parameters suggest that cows adopt varied metabolic adaptation strategies to cope with energy deficits postpartum. Our investigation found a comprehensive remodeling of the serum metabolic profiles in transition dairy cattle, highlighting the significance of alterations in sphingolipid species, as they play a crucial role in insulin resistance and metabolic disorders.
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Ceramidas , Lactancia , Lipólisis , Metaboloma , Periodo Posparto , Animales , Bovinos , Femenino , Periodo Posparto/sangre , Ceramidas/sangre , Ceramidas/metabolismo , Leche/metabolismo , Leche/química , Metabolismo de los Lípidos , Estudios Retrospectivos , Lipidómica , Lípidos/sangreRESUMEN
Objective: To investigate the role and underlying mechanisms of methyltransferase (Mettl) 3 in the process of angiotensin â ¡ (Ang â ¡)-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis. Methods: C57BL/6J mice were used, in cell experiments, mouse renal pericytes were isolated and cultured using magnetic bead sorting. These pericytes were then induced to transdifferentiate into myofibroblasts with 1×106 mmol/L Ang â ¡, which was the Ang â ¡ group, while pericytes cultured in normal conditions served as the control group. Successful transdifferentiation was verified by immunofluorescence staining, Western blotting, and real-time reverse transcription PCR (RT-qPCR) for α-smooth muscle actin (α-SMA). The levels of m6A modifications and related enzymes (Mettl3, Mettl14), Wilms tumor 1-associated protein (WTAP), fat mass and obesity protein (FTO), ALKBH5, YTHDF1, YTHDF2, YTHDC1, YTHDC2, YTHDC3 were assessed by Dot blot, RT-qPCR and Western blot. Mettl3 expression was inhibited in cells using lentivirus-mediated Mettl3-shRNA transfection, creating sh-Mettl3 and Ang â ¡+sh-Mettl3 groups, while lentivirus empty vector transfection served as the negative control (Ang â ¡+sh-NC group). The impact of Ang â ¡ on pericyte transdifferentiation was observed, and the expression of downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway proteins, including PI3K, AKT, phosphorylated AKT at serine 473 (p-AKT (S473)), and phosphorylated AKT at threonine 308 (p-AKT (T308)), were examined. PI3K gene transcription was inhibited by co-culturing cells with actinomycin D, and the half-life of PI3K mRNA was calculated by measuring residual PI3K mRNA expression over different co-culture time. The reversibility of Mettl3 inhibition on Ang â ¡-induced pericyte-to-myofibroblast transdifferentiation was assessed by adding the AKT activator SC79 to the Ang â ¡+sh-Mettl3 group. In animal experiments, mice were divided into these groups: sham group (administered 0.9% sterile saline), Ang â ¡ group (infused with Ang â ¡ solution), sh-Mettl3 group (injected with Mettl3 shRNA lentivirus solution), Ang â ¡+sh-Mettl3 group (infused with Ang â ¡ solution and injected with Mettl3 shRNA lentivirus solution), and Ang â ¡+sh-Mettl3+SC79 group (administered Ang â ¡ solution and Mettl3 shRNA lentivirus, with an additional injection of SC79). Each group consisted of six subject mice. Blood pressure was measured using the tail-cuff method before and after surgery, and serum creatinine, urea, and urinary albumin levels were determined 4 weeks post-surgery. Kidney tissues were collected at 28 days and stained using hematoxylin-eosin (HE) and Masson's trichrome to assess the extent of renal fibrosis. Results: Primary renal pericytes were successfully obtained by magnetic bead sorting, and intervened with 1×106 mmol/L Ang â ¡ for 48 hours to induce pericyte-to-myofibroblast transdifferentiation. Dot blot results indicated higher m6A modification levels in the Ang â ¡ group compared to the control group (P<0.05). RT-qPCR and Western blot results showed upregulation of Mettl3 mRNA and protein levels in the Ang â ¡ group compared to the control group (both P<0.05). In the Ang â ¡+sh-Mettl3 group, Mettl3 protein expression was lower than that in the Ang â ¡ group, with reduced expression levels of α-SMA, vimentin, desmin, fibroblast agonist protein (FAPa) and type â collagen (all P<0.05). Compared to the control group, PI3K mRNA expression level was elevated in the Ang â ¡ group, along with increased p-AKT (S473) and p-AKT (T308) expressions. In the Ang â ¡+sh-Mettl3 group, PI3K mRNA expression and p-AKT (S473) and p-AKT (T308) levels were decreased (all P<0.05). The half-life of PI3K mRNA was shorter in the Ang â ¡+sh-Mettl3 group than that in the Ang â ¡+sh-NC group (2.34 h vs. 3.42 h). The ameliorative effect of Mettl3 inhibition on Ang â ¡-induced pericyte-to-myofibroblast transdifferentiation was reversible by SC79. Animal experiments showed higher blood pressure, serum creatinine, urea, and 24-hour urinary protein levels, and a larger fibrosis area in the Ang â ¡ group compared to the sham group (all P<0.05). The fibrosis area was smaller in the Ang â ¡+sh-Mettl3 group than that in the Ang â ¡ group (P<0.05), but increased again upon addition of SC79. Conclusion: Mettl3-mediated RNA m6A epigenetic regulation is involved in Ang â ¡-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis, potentially by affecting PI3K stability and regulating the PI3K/AKT signaling pathway.
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Angiotensina II , Transdiferenciación Celular , Metiltransferasas , Ratones Endogámicos C57BL , Miofibroblastos , Pericitos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Pericitos/metabolismo , Metiltransferasas/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Angiotensina II/farmacología , Miofibroblastos/metabolismo , Riñón , Células CultivadasRESUMEN
This paper briefly introduces the unique advantages, overall analysis ideas and existing analysis methods of individual patient data Meta-analysis in terms of effect modification. In addition to Meta-regression and subgroup analysis, this paper also introduces the analysis methods based on part of individual patient data integrated with aggregated data and summarizes the current reporting of the above mentioned methods. In addition, the application and results interpretation of the above mentioned methods in individual patient data Meta-analysis are presented in this paper by taking "Effects of sodium-glucose cotransporter 2 inhibitors on SBP in patients with type 2 diabetes" as an example and by introducing their advantages and limitations.
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Diabetes Mellitus Tipo 2 , HumanosRESUMEN
This paper briefly introduces the characteristics, research significance, and global reporting status of effect modification in network Meta-analysis, demonstrates the heterogeneity caused by effect modification in network Meta-analysis, and emphasizes the importance of exploring effect modification in network Meta-analysis. This paper also summarizes the normalized description and analysis strategies of effect modification in network Meta-analysis. Finally, by the case of "comparison of efficacy of three new hypoglycemic drugs in reducing body weight in type 2 diabetes patients", this paper demonstrates the realization of subgroup analysis and network Meta-regression in exploring effect modification, summarizes the advantages and disadvantages of the two methods, to provide references for future researchers.
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Diabetes Mellitus Tipo 2 , Humanos , Metaanálisis en Red , Peso Corporal , Hipoglucemiantes/uso terapéuticoRESUMEN
This paper briefly introduces the definition, classification and significance of effect modification in epidemiological studies, summarizes the difference between effect modifier and confounders, and analyze the influence as well as the role of effect modification in epidemiological studies and Meta-analysis. In this paper, the possible scenarios of effect modification and related analysis strategy in Meta-analysis are indicated by graphics, aiming to arouse researchers' attention to effect modification. This paper also demonstrates how to identify and deal with effect modification in Meta-analysis through a study case of "Efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes", and shows the analysis process and interpretation of results of subgroup analysis and Meta-regression methods respectively. The advantages and disadvantages of these two methods are summarized to provide reference for the method selection of future research.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiologíaRESUMEN
Objective: To explore the optimal ratio of dihydrotestosterone and hydroxyflutamide (hereinafter referred to as DH), construct a dual release system of androgen and its antagonist, and analyze the application effect of this system in the repair of full-thickness burn wounds in mice. Methods: This study was an experimental study. The HaCaT cells were divided into blank group (without drug culture), low baseline group, medium baseline group, and high baseline group according to the random number table (the same grouping method below), and the last three groups of cells were cultured by adding three different ratios of DH. Under a medium ratio, the mass of dihydrotestosterone in the three baseline groups from low to high was 1.4, 2.8, and 4.0 µg, respectively, and the mass of hydroxyflutamide was 1.2, 1.6, and 2.0 µg, respectively. On this basis, under a small ratio, the mass of dihydrotestosterone was reduced by half and the mass of hydroxyflutamide was increased by half; under a large ratio, the mass of dihydrotestosterone was increased by half and the mass of hydroxyflutamide was reduced by half. After culture of 2 days, the cell proliferation level was detected by cell counting kit 8 (n=4). Sixteen 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into blank group, small ratio group, medium ratio group, and large ratio group, with 4 mice in each group. On post injury day (PID) 7, normal saline containing different ratios of DH was locally dropped to the wounds of mice in the last three groups of mice (the total mass of DH in the three ratio groups from small to large was 127.5, 165.0, and 202.5 µg, respectively, and the mass ratios of dihydrotestosterone to hydroxyflutamide (hereinafter referred to as drug mass ratio) were 8â¶9, 8â¶3, and 8â¶1, respectively), afterwards, the administration was repeated every 48 hours until PID 27; normal saline was dropped to the wound of mice in blank group at the aforementioned time points. The wound healing status on PID 0 (immediately), 7, 14, 21, and 28 was observed, and the wound healing rates on PID 7, 14, 21, and 28 were calculated (n=4). On PID 28, the wound tissue was taken, which was stained with hematoxylin and eosin for observing re-epithelialization and with Masson for observing collagen fibers, and the proportion of collagen fibers was analyzed (n=3). Twenty 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into ordinary scaffold group, small proportion scaffold group, medium proportion scaffold group, and large proportion scaffold group (with 5 mice in each group). On PID 7, the wound was continuously dressed with a polycaprolactone scaffold without drug and a polycaprolactone scaffold containing DH with a drug mass ratio of 1â¶3, 1â¶1, or 3â¶1 (i.e. the dual release system of androgen and its antagonist, with total mass of DH being about 1.7 mg) prepared by using electrospinning technology until the end of the experiment. Histopathological analyses of tissue (n=3) at the same time points as those in the previous animal experiment were performed. On PID 7 and 14, the wound exudates were collected and the relative abundance of bacterial communities was analyzed using 16S ribosomal RNA high-throughput sequencing (n=3). Results: After culture of 2 days, under a small ratio, the proliferation levels of HaCaT cells in low baseline group and high baseline group were significantly higher than the level in blank group (P<0.05). As the time after injury prolonged, the wounds of all four groups of mice continued to shrink. On PID 14, the wound healing rate of mice in large ratio group was 72.5% (61.7%, 75.1%), which was close to 53.3% (49.5%, 64.4%) in blank group (P>0.05); the wound healing rates of mice in small and medium ratio groups were 74.2% (71.0%, 84.2%) and 70.4% (65.1%, 74.4%), respectively, which were significantly higher than the rate in blank group (with both Z values being -2.31, P<0.05). On PID 21, the wound healing rate of mice in small ratio group was significantly higher than that in blank group (Z=-2.31, P<0.05). On PID 28, the wounds of mice in the three ratio groups were completely re-epithelialized and the epidermis was thicker than that in blank group; compared with that in blank group, the collagen fiber content in the wound tissue of mice in the three ratio groups was higher and arranged more orderly, and the proportions of collagen fibers in the wound tissue of mice in small and large ratio groups were significantly increased (P<0.05). On PID 28, the wounds of mice in ordinary scaffold group were partially epithelialized, while the wounds of mice in the three proportion scaffold groups were almost completely epithelialized. Among them, the wounds of mice in small proportion scaffold group had the thickest epidermis. The proportion of collagen fibers in the wound tissue of mice in small proportion scaffold group was significantly increased compared with that in ordinary scaffold group (P<0.05). On PID 7, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Corynebacterium, Staphylococcus, and Rhodococcus. On PID 14, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Stenotrophomonas, Rhodococcus, and Staphylococcus, and the number of bacterial species in the wound exudation of mice in the three proportion scaffold groups was more than that in ordinary scaffold group. Conclusions: When the drug mass ratio is relatively small, DH has the effect of promoting the proliferation of HaCaT cells. The ratio of 8â¶9 is the optimal mass ratio of dihydrotestosterone to hydroxyflutamide, and DH with this mass ratio can promote re-epithelialization and collagen deposition of full-thickness burn wounds in mice, and promote wound healing. The constructed dual release system of androgen and its antagonist with DH in a 1â¶3 drug mass ratio contributes to the re-epithelialization and collagen deposition of the full-thickness burn wounds in mice, and can improve the diversity of wound microbiota.
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Quemaduras , Flutamida/análogos & derivados , Traumatismos de los Tejidos Blandos , Ratones , Masculino , Animales , Cicatrización de Heridas , Andrógenos/farmacología , Dihidrotestosterona/farmacología , Solución Salina , Colágeno , Quemaduras/tratamiento farmacológicoRESUMEN
Objective: Randomized controlled trials (RCT) usually have strict implementation criteria. The included subjects' characteristics of the conditions for the intervention implementation are quite different from the actual clinical environment, resulting in discrepancies between the risk-benefit of interventions in actual clinical use and the risk-benefit shown in RCT. Therefore, some methods are needed to enhance the extrapolation of RCT results to evaluate the real effects of drugs in real people and clinical practice settings. Methods: Six databases (PubMed, Embase, Web of Science, CNKI, Wanfang Data, and VIP) were searched up to 31st December 2022 with detailed search strategies. A scoping review method was used to integrate and qualitatively describe the included literature inductively. Results: A total of 12 articles were included. Three methods in the included literature focused on: â improving the design of traditional RCT to increase population representation; â¡combining RCT Data with real-world data (RWD) for analysis;â¢calibrating RCT results according to real-world patient characteristics. Conclusions: Improving the design of RCT to enhance the population representation can improve the extrapolation of the results of RCT. Combining RCT data with RWD can give full play to the advantages of data from different sources; the results of the RCT were calibrated against real-world population characteristics so that the effects of interventions in real-world patient populations can be predicted.
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Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Proyectos de InvestigaciónRESUMEN
Objective: To explore the clinical effects of early rehabilitation treatment after repair surgery of skin and soft tissue defects accompanied by extensor tendon injury on the back of hand. Methods: This study was a retrospective non-randomized controlled study. From February 2015 to February 2023, 24 patients (15 males and 9 females, aged 12-55 years) with skin and soft tissue defects accompanied by extensor tendon injury on the back of hand, who met the inclusion criteria and were repaired with flap transplantation and tendon grafting or tendon anastomosis, were admitted to the First Affiliated Hospital of Air Force Medical University. According to different intervention time for postoperative rehabilitation treatment of patients, the patients were divided into conventional rehabilitation group and early rehabilitation group, with 12 cases in each group. Patients in early rehabilitation group received rehabilitation treatment immediately after surgery under the rehabilitation guidance of specialized rehabilitation physicians based on the characteristics of different postoperative periods. Patients in conventional rehabilitation group began rehabilitation treatment from the third week after surgery, and their rehabilitation treatment was the same as that of patients in early rehabilitation group from the second week after surgery. The patients in 2 groups were treated in the hospital until the sixth week after surgery. The occurrence of flap vascular crisis and tendon rupture were observed within 6 weeks after surgery. After 6 weeks of surgery, the manual muscle test was used to measure the pinching force between the index finger and thumb, lateral pinching force, three-point pinching force, and grip force of the affected hand; the total action motion method was used to evaluate the finger joint range of motion of the affected hand, and the excellent and good ratio was calculated; the Carroll upper extremity function test was used to score and rate the function of the affected hand. Results: Within 6 weeks after surgery, only 1 patient in conventional rehabilitation group suffered from venous crisis, and the flap survived after the second surgical exploration and anastomosis of blood vessels; there was no occurrence of tendon rupture in patients of 2 groups. After 6 weeks of surgery, there were no statistically significant differences in pinching force between the index finger and thumb, lateral pinching force, three-point pinching force, or grip force of the affected hand between the two groups of patients (P>0.05); the excellent and good ratio of the finger joint range of motion of the affected hand of patients in early rehabilitation group was 11/12, which was higher than 7/12 in conventional rehabilitation group, but there was no statistically significant difference (P>0.05); the affected hand function score of patients in early rehabilitation group was 90±6, which was significantly higher than 83±8 in conventional rehabilitation group (t=2.41, P<0.05); the function rating of the affected hand of patients in early rehabilitation group was obviously better than that in conventional rehabilitation group (Z=2.04, P<0.05). Conclusions: Early rehabilitation treatment for patients with skin and soft tissue defects accompanied by extensor tendon injury on the back of hand after repair surgery can improve hand function, but it would not increase surgery related complications, which is worthy of clinical promotion and application.
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Traumatismos de los Tejidos Blandos , Colgajos Quirúrgicos , Traumatismos de los Tendones , Humanos , Masculino , Femenino , Adulto , Estudios Retrospectivos , Traumatismos de los Tendones/rehabilitación , Traumatismos de los Tendones/cirugía , Persona de Mediana Edad , Traumatismos de los Tejidos Blandos/cirugía , Traumatismos de los Tejidos Blandos/rehabilitación , Colgajos Quirúrgicos/cirugía , Adolescente , Traumatismos de la Mano/cirugía , Traumatismos de la Mano/rehabilitación , Adulto Joven , Mano/cirugía , Niño , Piel/lesiones , Tendones/cirugía , Procedimientos de Cirugía Plástica/métodos , Trasplante de Piel/métodosRESUMEN
Objective: Differences between randomized controlled trial (RCT) results and real world study (RWS) results may not represent a true efficacy-effectiveness gap because efficacy-effectiveness gap estimates may be biased when RWS and RCT differ significantly in study design or when there is bias in RWS result estimation. Secondly, when there is an efficacy- effectiveness gap, it should not treat every patient the same way but assess the real-world factors influencing the intervention's effectiveness and identify the subgroup likely to achieve the desired effect. Methods: Six databases (PubMed, Embase, Web of Science, CNKI, Wanfang Data, and VIP) were searched up to 31st December 2022 with detailed search strategies. A scoping review method was used to integrate and qualitatively describe the included literature inductively. Results: Ten articles were included to discuss how to use the RCT research protocol as a template to develop the corresponding RWS research protocol. Moreover, based on correctly estimating the efficacy-effectiveness gap, evaluate the intervention effect in the patient subgroup to confirm the subgroup that can achieve the expected benefit-risk ratio to bridge the efficacy-effectiveness gap. Conclusion: Using real-world data to simulate key features of randomized controlled clinical trial study design can improve the authenticity and effectiveness of study results and bridge the efficacy-effectiveness gap.
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Proyectos de Investigación , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Objective: To construct a diabetes foot prediction model for adult patients with type 2 diabetes based on retrospective cohort study using data from a regional health data platform. Methods: Using Yinzhou Health Information Platform of Ningbo, adult patients with newly diagnosed type 2 diabetes from January 1, 2015 to December 31, 2022 were included in this study and divided randomly the train and test sets according to the ratio of 7â¶3. LASSO regression model and bidirectional stepwise regression model were used to identify risk factors, and model comparisons were conducted with net reclassification index, integrated discrimination improvement and concordance index. Univariate and multivariate Cox proportional hazard regression models were constructed, and a nomogram plot was drawn. Area under the curve (AUC) was calculated as a discriminant evaluation indicator for model validation test its calibration ability, and calibration curves were drawn to test its calibration ability. Results: No significant difference existed between LASSO regression model and bidirectional stepwise regression model, but the better bidirectional stepwise regression model was selected as the final model. The risk factors included age of onset, gender, hemoglobin A1c, estimated glomerular filtration rate, taking angiotensin receptor blocker and smoking history. AUC values (95%CI) of risk outcome prediction at year 5 and 7 were 0.700 (0.650-0.749) and 0.715(0.668-0.762) for the train set and 0.738 (0.667-0.801) and 0.723 (0.663-0.783) for the test set, respectively. The calibration curves were close to the ideal curve, and the model discrimination and calibration powers were both good. Conclusions: This study established a convenient prediction model for diabetic foot and classified the risk levels. The model has strong interpretability, good discrimination power, and satisfactory calibration and can be used to predict the incidence of diabetes foot in adult patients with type 2 diabetes to provide a basis for self-assessment and clinical prediction of diabetic foot disease risk.
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Diabetes Mellitus Tipo 2 , Pie Diabético , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Pie Diabético/epidemiología , Estudios Retrospectivos , Incidencia , Factores de Riesgo , Masculino , Femenino , Modelos de Riesgos Proporcionales , Nomogramas , Persona de Mediana Edad , Hemoglobina Glucada/análisis , AdultoRESUMEN
BACKGROUND: APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors. PATIENTS AND METHODS: Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials. RESULTS: In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%. CONCLUSIONS: APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors.
RESUMEN
Objective: To explore the effect of exercise prescription based on a progressive mode in treating elderly patients with lower limb dysfunction after deep burns. Methods: A randomized controlled trial was conducted. From January 2021 to January 2023, 60 elderly patients with lower limb dysfunction after deep burns who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University. The patients were divided into conventional rehabilitation group (30 cases, 17 males and 13 females, aged (65±3) years) and combined rehabilitation group (30 cases, 16 males and 14 females, aged (64±3) years) according to the random number table. For patients in both groups, the red-light treatment was started after the lower limb wounds healed or when the total area of scattered residual wounds was less than 1% of the total body surface area. After 2 weeks of red-light treatment, the patients in conventional rehabilitation group were given conventional rehabilitation treatments, including joint stretching, resistance, and balance training; in addition to conventional rehabilitation treatments, the patients in combined rehabilitation group were given exercise prescription training based on a progressive mode three times a week, mainly including dumbbell press, Bobath ball horizontal support, and high-level pulldown trainings. The training time for patients in both groups was 12 weeks. Before training (after 2 weeks of red-light treatment) and after 12 weeks of training, the upper limb and lower limb motor functions of the patients were evaluated using the simple Fugl-Meyer scale, the physical fitness of patients was evaluated using the simple physical fitness scale, and the patient's risk of falling was evaluated by the time consumed for the timed up and go test. The adverse events of patients that occurred during training were recorded. After 12 weeks of training, a self-designed satisfaction survey was conducted to investigate patients' satisfaction with the training effect. Data were statistically analyzed with independent sample t test, paired sample t test, Mann-Whitney U test, Wilcoxon signed rank test, and chi-square test. Results: Before training, the scores of upper limb and lower limb motor functions of patients between the two groups were similar (P>0.05). After 12 weeks of training, the scores of upper limb motor function of patients in conventional rehabilitation group and combined rehabilitation group were significantly higher than those before training (with t values of -11.42 and -13.67, respectively, P<0.05), but there was no statistically significant difference between the two groups (P>0.05). The score of lower limb motor function of patients in combined rehabilitation group was 28.9±2.6, which was significantly higher than 26.3±2.6 in conventional rehabilitation group (t=-3.90, P<0.05), and the scores of lower limb motor function of patients in conventional rehabilitation group and combined rehabilitation group were significantly higher than those before training (with t values of -4.14 and -6.94, respectively, P<0.05). Before training, the individual and total scores of physical fitness of patients between the two groups were similar (P>0.05). After 12 weeks of training, the balance ability score, walking speed score, chair sitting score, and total score of physical fitness of patients in conventional rehabilitation group and combined rehabilitation group were significantly increased compared with those before training (with Z values of -4.38, -3.55, -3.88, -4.65, -4.58, -4.68, -4.42, and -4.48, respectively, P<0.05), and the balance ability score, walking speed score, chair sitting score, and total score of physical fitness of patients in combined rehabilitation group were significantly increased compared with those in conventional rehabilitation group (with Z values of -3.93, -3.41, -3.19, and -5.33, P<0.05). Before training, the time consumed for the timed up and go test for patient's risk of falling in the two groups was close (P>0.05). After 12 weeks of training, the time consumed for the timed up and go test for patient's risk of falling in combined rehabilitation group was (28.0±2.1) s, which was significantly shorter than (30.5±1.8) s in conventional rehabilitation group (t=4.94, P<0.05). Moreover, the time consumed for the timed up and go test for patient's risk of falling in both conventional rehabilitation group and combined rehabilitation group was significantly shorter than that before training (with t values of 14.80 and 15.86, respectively, P<0.05). During the training period, no adverse events such as muscle tissue strain, edema, or falling occurred in any patient. After 12 weeks of training, the satisfaction score of patients with the training effect in combined rehabilitation group was 13.5±1.2, which was significantly higher than 8.5±1.4 in conventional rehabilitation group (t=21.78, P<0.05). Conclusions: The exercise prescription training based on a progressive mode can significantly promote the recovery of lower limb motor function and physical fitness of elderly patients with lower limb dysfunction after deep burns, and effectively reduce the patient's risk of falling without causing adverse events during the training period, resulting in patient's high satisfaction with the training effect.