Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is an uncommon congenital developmental disorder distinguished by intellectual disorder and distinctive facial characteristics, with a minority of cases attributed to RAD21 variants. METHODS: A patient was admitted to the endocrinology department at Peking Union Medical College Hospital, where 2 mL of peripheral venous blood was collected from the patient and his parents. DNA was extracted for whole-exome sequencing (WES) analysis, and the genetic variation of the parents was confirmed through Sanger sequencing. RESULTS: A 13.3-year-old male patient with a height of 136.5 cm (-3.5 SDS) and a weight of 28.4 kg (-3.1 SDS) was found to have typical craniofacial features. WES revealed a pathogenic variant c.1143G>A (p.Trp381*) in the RAD21 gene. He was diagnosed with CdLS type 4 (OMIM #614701). We reviewed 36 patients with CdLS related to RAD21 gene variants reported worldwide from May 2012 to March 2024. Patient's variant status, clinical characteristics, and rhGH treatment response were summarized. Frameshift variants constituted the predominant variant type, representing 36% (13/36) of cases. Clinical features included verbal developmental delay and intellectual disorder observed in 94% of patients. CONCLUSION: This study reported the third case of CdLS type 4 in China caused by a RAD21 gene variant, enriching the genetic mutational spectrum.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

No causal association between the volume of strenuous exercise and coronary atherosclerosis: a two-sample Mendelian randomization study.

Objective: Several observational studies have shown that high-volume and high-intensity exercise training increases the prevalence and severity of coronary atherosclerosis, but the causal effect still remains uncertain. This study aims to explore the causal relationship between the volume of strenuous exercise (SE) and coronary atherosclerosis (CA) using the Mendelian randomization (MR) method. Method: The exposure factors were two basic parameters of the volume of strenuous exercise (duration and frequency of strenuous exercise), the outcome factor was coronary atherosclerosis, and the relevant genetic loci were extracted from the summary data of the genome-wide association study (GWAS) as the instrumental variables, and MR analyses were performed using the inverse variance weighting (IVW) method, the weighted median method, and the MR-egger method. Sensitivity analyses were performed using heterogeneity analysis, pleiotropy analysis, and the "leave-one-out" method. The original results were tested using other coronary atherosclerosis data sets. Result: IVW results showed no causal association between duration of strenuous exercise (DOSE) [OR = 0.9937, 95% CI (0.9847, 1.0028), P = 0.1757] and frequency of strenuous exercise (FOSE) in the last 4 weeks [OR = 0.9930, 95% CI (0.9808, 1.0054), P = 0.2660] and coronary atherosclerosis. All of the above results were validated with other coronary atherosclerosis data sets. Conclusion: The present study supports that the causal association of duration and frequency of SE with CA was not found, and provides valuable insights into the choice of scientific and correct volume of SE to cardiac rehabilitation (CR).

Bone mineral density in adults growth hormone deficiency with different ages of onset: a real-world retrospective study.

PURPOSE: Bone mineral density (BMD) impairment is one of the critical factors for long-term quality of life in adults growth hormone deficiency (AGHD). This study aims to investigate the annual changes in BMD in AGHD patients with different ages of onset and to identify predicting factors that influence BMD. METHODS: AGHD patients (n = 160) with available data for 4 years follow-up from a major tertiary medical center in China were retrospectively included (110 [68.8%] childhood-onset, 119 [74.4%] male). BMD of the axial bone (including total hip, neck of femur, and L1-4) derived from dual X-ray absorptiometry and final height were investigated at the first visit, 12 months, 24 months, 36 months, and 48 months thereafter. Low BMD was defined as Z-score ≤ -2. RESULTS: The prevalence of low BMD was 30.0% at baseline and 12.5% at 4 years of follow-up. The CO AGHD group presented a significantly lower BMD than the AO AGHD group at the baseline (P = 0.009). In contrast, the CO AGHD group had significantly greater median annual BMD change than the AO AGHD group (0.044 vs. -0.0003 g/cm2/year in L1-4, P < 0.001), indicating a significant difference in the overall BMD trend between CO and AO groups. Childhood-onset (odds ratio [OR] 0.326, P = 0.012), low serum testosterone (OR 0.847; P = 0.004) and FT4 (OR 0.595; P = 0.039) level were independent risk factors for BMD loss. CONCLUSION: The annual changes of BMD show a different pattern in AGHD patients with varying ages of onset. Patients with CO AGHD have a lower bone mass, and in general, appropriate replacement therapy is necessary for long-term bone health in AGHD patients.

The distinct hepatic metabolic profile and relation with impaired liver function in congenital isolated growth hormone-deficient rats.

Objective: Patients with growth hormone deficiency (GHD) with inadequate growth hormone levels are often correlated with nonalcoholic fatty liver disease (NAFLD). However, the potential mechanism of how GHD influences liver function remains obscure. In the present study, we aim to perform hepatic metabolomics in Lewis dwarf rats, which were the standard congenital isolated GH-deficient rat, to evaluate the characterizations of hepatic metabolic profiles and explore their relations with liver functions. Methods: Lewis dwarf homozygous (dw/dw) rats at 37 weeks (five females and five males), and Lewis dwarf heterozygous (dw/+) rats at 37 weeks (five females and five males) were analyzed in our study. Body lengths and weights, liver weights, serum alanine transaminase (ALT), and serum aspartate transaminase (AST) were measured. ELISA and RT-qPCR were used to assess IGF-1 levels in serum and liver, respectively. The non-targeted metabolomics was performed in the livers of dw/+ and dw/dw rats. Differential metabolites were selected according to the coefficient of variation (CV), variable importance in the projection (VIP) > 1, and P < 0.05. Hierarchical clustering of differential metabolites was conducted, and the KEGG database was used for metabolic pathway analysis. Results: The body weights, body lengths, liver weights, and IGF-1 levels in the serum and liver of dw/dw rats were significantly decreased compared with dw/+ rats. Dw/dw rats exhibited more obvious hepatic steatosis accompanied by higher serum ALT and AST levels. Hepatic metabolomics showed that a total of 88 differential metabolites in positive ion mode, and 51 metabolites in negative ion mode were identified. Among them, lysophosphatidylcholine (LPC) 16:2, LPC 18:3, LPC 22:6, fatty acid esters of hydroxy fatty acids (FAHFA)18:1 were significantly decreased, while palmitoyl acid, dehydrocholic acid, and 7-ketolithocholic acid were significantly increased in dw/dw rats compared with dw/+ rats. These seven differential metabolites were significantly associated with phenotypes of rats. Finally, KEGG pathway analysis showed that the arginine and proline metabolism pathway and bile secretion pathway were mainly clustered. Conclusion: Lewis dw/dw rats with congenital isolated growth hormone deficiency (IGHD) showed liver steatosis and abnormal liver function, which could be potentially associated with the distinctive hepatic metabolic profiles.

Serum prolactin levels were positively related to metabolic indexes and disorders in male obese patients.

PURPOSE: The role of prolactin (PRL) in glucolipid metabolism was inconsistent, and there were few studies on the metabolic role of PRL in obese patients. The study aims to explore association between PRL level and metabolic disorders in male obese patients. METHODS: A retrospective study was conducted. Eighty-nine male patients with obesity were included, and their clinical data were recorded. RESULTS: A total of 89 male obese patients were included in this study. Their average age was 24.5 ± 9.0 years and BMI was 42.8 ± 9.1 kg/m2. The average waist circumference and body fat percentage was 129.6 ± 19.6 cm and 42.9 ± 8.0%, respectively. The median prolactin levels were 10.0 ng/ml (range: 3.93-30.1 ng/ml). 79.0% (49/62) of these patients presented with NAFLD and 77.3% (68/88) of them was dyslipidemia. Further, serum prolactin level was positively correlated with BMI (r = 0.225, P = 0.034), body fat percentage (r = 0.326, P = 0.017), ALT (r = 0.273, P = 0.011) and AST (r = 0.245, P = 0.029). Compared with low PRL group (<10 ng/ml), the incidence of morbid obesity and NAFLD was higher in high PRL group (morbid obesity: 71.1% vs 45.5%, P = 0.018 and NAFLD: 91.2% vs 64.3%, P = 0.013). In addition, the risk of NAFLD and morbid obesity in high PRL group (>10 ng/ml) was higher than low PRL group (OR:5.187, 95%CI 1.194-22.544, P = 0.028 and OR: 4.375, 95% CI 1.595-11.994, P = 0.004). The increased risk of NAFLD and morbid obesity in the high PRL group still existed after adjusting for age and Testosterone. CONCLUSION: Serum prolactin levels were positively associated with deterioration of metabolic indexes in male obese patients, as well as NAFLD and morbid obesity.

Bacterial Efflux Pump Inhibitors Reduce Antibiotic Resistance.

Bacterial resistance is a growing problem worldwide, and the number of deaths due to drug resistance is increasing every year. We must pay great attention to bacterial resistance. Otherwise, we may go back to the pre-antibiotic era and have no drugs on which to rely. Bacterial resistance is the result of several causes, with efflux mechanisms widely recognised as a significant factor in the development of resistance to a variety of chemotherapeutic and antimicrobial medications. Efflux pump inhibitors, small molecules capable of restoring the effectiveness of existing antibiotics, are considered potential solutions to antibiotic resistance and have been an active area of research in recent years. This article provides a review of the efflux mechanisms of common clinical pathogenic bacteria and their efflux pump inhibitors and describes the effects of efflux pump inhibitors on biofilm formation, bacterial virulence, the formation of bacterial persister cells, the transfer of drug resistance among bacteria, and mismatch repair. Numerous efforts have been made in the past 20 years to find novel efflux pump inhibitors which are known to increase the effectiveness of medicines against multidrug-resistant strains. Therefore, the application of efflux pump inhibitors has excellent potential to address and reduce bacterial resistance.

Clinical Characteristics and Outcomes of Prolactinomas in Children and Adolescents: A Large Retrospective Cohort Study.

CONTEXT: Prolactinoma, the most common subtype of pituitary adenoma, is rare in children and adolescents. Clinical presentation and treatment outcomes of prolactinomas in this population have been evaluated insufficiently. OBJECTIVE: To summarize the clinical features, both medication and surgical outcomes of prolactinomas in children and adolescents in a large retrospective cohort from China. METHODS: A cohort of patients with prolactinomas aged ≤20 years at diagnosis between 2012 and 2021 in Peking Union Medical College Hospital were retrospectively analyzed. RESULTS: The cohort comprised 170 patients (115 females and 55 males, median age 16.6 years), with 20.0% (23/115) girls without menarche and 33.3% (18/54) boys in prepuberty. The median maximal diameter was 15.0 mm (61.2% macroadenomas and 4.6% giant adenomas), and the median baseline prolactin (PRL) level was 211.0 ng/mL. Larger sizes and higher PRL levels were observed in girls without menarche at diagnosis and in boys. Most girls presented with menstrual disturbance (86.7%), and boys were frequently bothered by headaches (42.6%), reduced height velocities (25.9%), and delayed puberty (18.2%). Dopamine agonists (DAs) were used as first-line treatment in 133 patients, and the resistance rate was 22.5% (25/111), independently associated with maximal tumor diameters (P = .035). Surgery was performed in 76 patients. Long-term surgical remission rates were 32.9% (25/76) overall, negatively associated with cavernous sinus invasion independently (P = .025), 59.4% (19/32) in noninvasive tumors (64.0% in 25 noninvasive macroadenomas), and 5.0% (1/20) in invasive tumors. CONCLUSION: Pediatric prolactinomas exhibited more severe clinical characteristics in boys and in patients diagnosed during earlier stages of pubertal developments. Given the overall efficacy of PRL normalization by medication and considerable surgical remission rate in noninvasive tumors, DAs remain the first-line recommendation for prolactinomas in children and adolescents, while surgery might be viable for noninvasive tumors.

Immune cells in adipose tissue microenvironment under physiological and obese conditions.

PURPOSE: This review will focus on the immune cells in adipose tissue microenvironment and their regulatory roles in metabolic homeostasis of adipose tissue and even the whole body under physiological and obese conditions. METHODS: This review used PubMed searches of current literature to examine adipose tissue immune cells and cytokines, as well as the complex interactions between them. RESULTS: Aside from serving as a passive energy depot, adipose tissue has shown specific immunological function. Adipose tissue microenvironment is enriched with a large number of immune cells and cytokines, whose physiological regulation plays a crucial role for metabolic homeostasis. However, obesity causes pro-inflammatory alterations in these adipose tissue immune cells, which have detrimental effects on metabolism and increase the susceptibility of individuals to the obesity related diseases. CONCLUSIONS: Adipose tissue microenvironment is enriched with various immune cells and cytokines, which regulate metabolic homeostasis of adipose tissue and even the whole body, whether under physiological or obese conditions. Targeting key immune cells and cytokines in adipose tissue microenvironment for obesity treatment becomes an attractive research point.

Cerebrospinal Fluid Metabolomic Pattern of Different Pituitary Stalk Lesions.

OBJECTIVE: To describe the cerebrospinal fluid (CSF) metabolomic pattern of pituitary stalk lesions. METHODS: CSF was collected from patients with different pituitary stalk lesions treated at Peking Union Medical College Hospital: germ cell tumor (GCT, n = 27); hypophysitis (n = 10); and Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) (LCH + ECD, n = 10). The CSF metabolome profiles were characterized by liquid chromatography-mass spectrometry (LC-MS). RESULTS: There were 44 metabolites that significantly differed between patients with GCT and those with hypophysitis (P < .05). Between patients with GCT with CSF level of beta subunit of human chorionic gonadotrophin (ß-hCG) < 5 mIU/mL and those with hypophysitis, there were 15 differential metabolites (P < .05, fold change > 1.5 or < 1/1.5). All of the metabolites had an area under the curve (AUC) above 0.7. There were 9 metabolites that significantly differed between patients with GCT and those with LCH + ECD (P < .05) and 7 metabolites had significant differences between GCT (CSF ß-hCG < 5 mIU/mL) and LCH + ECD (P < .05, fold change > 1.5 or < 1/1.5). We found 6 metabolites that were significantly different between patients with hypophysitis and those with LCH + ECD (P < .05) and 5 of these had fold change more than 1.5 or less than 1/1.5. Three metabolites, 5-deoxydiplosporin, cloversaponin I, and phytosphingosine, showed excellent capabilities to differentiate the 3 disease categories. Furthermore, we identified 67 metabolites associated with clinical test results (ρ > 0.2, P < .05) and 29 metabolites showed strong correlation (ρ > 0.4, P < .05). CONCLUSION: Our study is the first to systematically investigate the metabolomics of CSF in different pituitary stalk lesions. CSF metabolomics is a useful strategy for biomarker discovery.

Brain white matter alterations in young adult male patients with childhood-onset growth hormone deficiency: a diffusion tensor imaging study.

PURPOSE: This study aimed to detect white matter changes and different effects of thyroid hormone on the white matter integrity in young adult male patients with childhood-onset growth hormone deficiency (CO-GHD), compared with healthy people. METHODS: Magnetic resonance imaging (structural imaging and diffusion tensor imaging) was performed in 17 young adult male patients with CO-GHD and 17 healthy male controls. The white matter volume, mean diffusivity (MD) values and fractional anisotropy (FA) values were quantified and compared between two groups (CO-GHD group vs. control group). We assessed the interaction effects between thyroid hormone and groups (CO-GHD group vs. control group) on white matter integrity. RESULTS: Patients with CO-GHD exhibited similar white matter volumes compared with controls. However, compared with the controls, patients with CO-GHD showed a significant reduction in FA values in six clusters and a substantial increase in MD values in four clusters, mainly involving the corticospinal tracts, corpus callosum and so on. Moreover, after correcting for insulin-like growth factor-1 levels, the significant interaction effects between groups (CO-GHD group vs. control group) and serum free thyroxine levels on MD values were noted in three clusters, mainly involving in superior longitudinal fasciculus and sagittal stratum. CONCLUSION: In conclusion, young males with CO-GHD showed white matter changes in multiple brain regions and different effects of thyroid hormone on the white matter integrity.

Clinical characteristics of male prolactinoma patients mainly presenting with severe obesity and the metabolic response to dopamine agonist therapy.

Objective: To summarize the clinical characteristics of 4 male prolactinoma patients with severe obesity. Methods: The clinical data of all the patients were retrospectively analyzed. Results: All the patients visited our hospital for severe obesity at the age of 16-30 years old with their body mass index (BMI) of 37.9-55.9 kg/m2. All the patients were obese since childhood, even at birth. Hyperprolactinemia (72.3-273.0 ng/ml) was found during the etiological screening of obesity and MRI revealed pituitary adenomas. Additionally, all of them had multiple obesity related complications, such as hyperinsulinemia and dyslipidemia. Treatment of dopamine agonists (DAs) effectively normalized their prolactin level and the pituitary MRI reexamination after 6 months of DAs treatment showed the shrinkage of the pituitary adenomas in 3 patients. Their weight also decreased in different degrees (2.70~19.03% lower than the baseline) with improved metabolic profiles. Conclusion: Serum prolactin level should be screened in obese patients, especially those with severe obesity.

Efficacy and safety of Chinese medicine injections in combination with docetaxel and cisplatin for non-small cell lung cancer: a network meta-analysis.

Background: Non-small cell lung cancer (NSCLC) poses a serious threat to human health. Several clinical studies have reported the benefits of Chinese herbal injections (CHIs) in combination with docetaxel and cisplatin (DP). This multidimensional network meta-analysis aimed to investigate the preferred regimen of CHIs in combination with DP for the treatment of NSCLC. Methods: Multiple databases were searched to identify randomized controlled trials (RCTs) of CHIs for NSCLC from the database inception to 30 April 2023. Studies that met the inclusion criteria and exhibited good methodological quality were included. Data analysis was conducted using Stata 15.0 and R 4.2.1 software. An odds ratio (OR) was used as the effect size, and the surface under the cumulative ranking curve (SCURA) was employed to rank the evaluated treatments. Results: The network meta-analysis included 85 eligible RCTs, encompassing 6,580 patients and 11 CHIs. Astragalus Injection combined with DP was identified as the most effective regimen for improving the response rate (SUCRAs: 90.25%). Brucea Javanica Oil Milk Injection combined with DP proved most effective in ameliorating the quality of life (SUCRAs: 76.89%). Shenfu Injection combined with DP emerged as the most effective for enhancing CD3+ and CD4+ (SUCRAs: 93.75%, 88.50%). Kanglaite Injection combined with DP exhibited the best efficacy in improving CD8+ (SUCRAs: 88.96%). Brucea Javanica Oil Milk Injection combined with DP was the most potent regimen for enhancing CD4+/CD8+ (SUCRAs: 93.13%). Conclusion: CHIs in combination with DP outperformed DP alone in NSCLC patients. Astragalus Injection plus DP, Brucea Javanica Oil Milk Injection plus DP, Shenfu Injection plus DP, Kanglaite Injection plus DP, and Brucea Javanica Oil Milk Injection plus DP were significantly effective. However, further multicenter and well-designed RCTs are required to validate our findings.

Explorative research on glucolipid metabolism and levels of adipokines in pseudohypoparathyroidism type 1 patients.

BACKGROUND: Pseudohypoparathyroidism type 1 (PHP1) is a rare disease featuring hypocalcemia and elevated PTH level. Though disturbed calcium and phosphorus metabolism under PTH resistant have been widely studied, glucolipid metabolism abnormalities observed in PHP1 patients have received little attention. The aim of this research is to explore the glucolipid metabolism features in a rather large cohort of PHP1 patient. In the current study, PHP1 patients and primary hyperparathyroidism patients as well as normal control were recruited for the investigation. Glucolipid metabolic indices as well as the level of four adipokines were examined. RESULTS: A total of 49 PHP1 patients, 64 PHPT patients and 30 healthy volunteers were enrolled. A trend of higher HOMA-ß index was found in PHP1 patients than normal controls (median 97.08% vs 68.19%, p = 0.060). Both the PHP1 and PHPT group presented with significantly lower TNFα level compared to normal controls (average 10.74 pg/ml and 12.53 pg/ml vs 15.47 pg/ml, p = 0.002 and 0.041, respectively). FGF21 level was significantly higher in PHPT group than in PHP1 group (median 255.74 pg/ml vs 167.46 pg/ml, p = 0.019). No significant difference in glucolipid metabolic indices and adipokines was found between PHP1A or PHP1B patients and normal controls, while overweight/obese PHP1 patients tended to have higher leptin than normal-BMI cases (p = 0.055). Multiple linear regression analysis showed BMI rather than PTH or HOMA-IR to be an independent variable of leptin in PHP1. CONCLUSION: Metabolic stress given upon especially overweight PHP1 patients may resulted in possible ß-cell compensation. Elevated TNFα may be related with hyper-PTH level regardless of calcium level.

Magnetic resonance imaging of knees: a novel approach to predict recombinant human growth hormone therapy response in short-stature children in late puberty.

BACKGROUND: There is no appropriate tool to predict recombinant human growth hormone (rhGH) response before therapy initiation in short-stature children in late puberty. The current study aimed to explore the associations between magnetic resonance imaging (MRI) stages of the knee growth plates and rhGH response in short-stature children in late puberty. METHODS: In this prospective cohort study, short-stature children in late puberty were treated with rhGH and followed up for 6 months. We proposed a novel knee MRI staging system according to the growth plate states of distal femurs or proximal tibias and divided the participants into three groups: unclosed growth plate group, marginally closed growth plate group, and nearly closed growth plate group. The primary outcomes were height gain and growth velocity (GV), which were assessed three months later. RESULTS: Fifty participants were enrolled, including 23 boys and 27 girls. GV and height gain after 6 months of rhGH therapy decreased successively in the three groups with an increased degree of growth plate fusion, especially when grouped by proximal tibias (GV1-3 mon from 9.38 to 6.08 to 4.56 cm/year, GV4-6 mon from 6.75 to 4.92 to 3.25 cm/year, and height gain from 4.03 to 2.75 to 1.95 cm, all P < 0.001). Moreover, the MRI stages of growth plates independently served as a significant variable for GV and height gain after therapy, especially when grouped by proximal tibias (all P < 0.01). CONCLUSION: The MRI staging method is expected to be an effective tool for predicting rhGH response before therapy initiation in short-stature children in late puberty.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

PURPOSE: Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40 mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. METHODS: Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39 mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. RESULTS: Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1 week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36 months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. CONCLUSIONS: With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

Intragastric Safflower Yellow Alleviates HFD Induced Metabolic Dysfunction-Associated Fatty Liver Disease in Mice through Regulating Gut Microbiota and Liver Endoplasmic Reticulum Stress.

The gut microbiota was reported to play a significant role in the progression of the metabolic associated fatty liver disease (MAFLD). Our recent study suggested that gastrointestinal tract and liver were important targets mediating the anti-obesity effects of intragastric safflower yellow (SY). Therefore, our present study aims to investigate the effect of intragastric SY on MAFLD and possible mechanism. DIO mice were treated with 125 mg/kg/d SY for 12 weeks by gavage. We found intragastric SY significantly slowed weight gain of body, reduced the food intake and liver weight, improved hepatic steatosis, liver function and glucose metabolism in DIO mice. The comparison between OGTT and IPGTT illustrated OGTT produced a better improvement of glucose tolerance after SY treatment. We also found intragastric SY significantly increased the energy expenditure and locomotor activity of DIO mice. SY obviously decreased the expression of lipogenesis-associated and ERS-related genes in liver of DIO mice and PA-induced MAFLD hepatocyte model. Gut microbiota analysis demonstrated intragastric SY apparently changed the diversity and composition of gut microbiota of DIO mice. Further function prediction analysis indicated that gut microbiotas in SY-treated mice was positively related with energy metabolism, lipid metabolism and endocrine system. Intragastric SY has a significant therapeutic effect on MAFLD, which is mediated partly by modulating gut microbiota and improving liver ERS.

Incidence and risk factors of cancers in acromegaly: a Chinese single-center retrospective study.

PURPOSE: To evaluate the incidence of malignancies in acromegaly and to identify risk factors for newly-diagnostic cancers, especially the excessive growth hormone (GH) and insulin-like growth factor-1 (IGF-1). METHODS: A retrospective cohort including 1738 consecutive hospitalized patients with acromegaly in a single referral center between 2012 and 2020 (mean follow-up 4.3 years). A gender- and age-matched case-control study (280 patients from the cohort) was performed for risk factor analysis. RESULTS: One hundred thirteen malignancies (67 diagnosed after acromegaly) were observed. The overall newly-diagnostic cancer risk of acromegaly was higher than the general population (standardized incidence ratio (SIR) 2.81; 95% CI 2.18-3.57). The risk of thyroid cancer (n = 33, SIR 21.42; 95% CI 13.74-30.08) and colorectal cancer (n = 8, SIR 3.17; 95% CI 1.37-6.25) was elevated. In the overall cohort, IGF-1 (ULN: 1.27 vs. 0.94, p = 0.057), GH (1.30 vs. 1.00 ng/ml, p = 0.12), and disease-controlled rate (34.9% vs. 45.9%, p = 0.203) at the last visit did not reach significance between patients with and without post-diagnostic cancer. In the case-control study, GH (1.80 vs. 0.90 ng/ml, p = 0.018) and IGF-1 (ULN: 1.27 vs. 0.91, p = 0.003) at the last visit were higher in patients with post-diagnostic cancers, with a lower disease-controlled rate. Elder age was a risk factor for cancer. Other metabolic comorbidities and the size of pituitary tumors were similar. CONCLUSION: The risk of malignancies, especially thyroid cancer, was increased in patients with acromegaly in our center. More cancer screening should be considered when managing acromegaly, especially in patients with higher posttreatment GH and IGF-1.

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs.

INTRODUCTION: Somatotroph pituitary neuroendocrine tumours (PitNETs) are characterized by complex and variable biological behaviours with unpredictable patterns of growth and invasiveness. The molecular mechanisms and reliable predictors of biological markers of invasiveness remain unknown. METHODS: Seventy-two acromegaly patients were consecutively enrolled. Data-independent acquisition-based proteomics and ingenuity pathway analysis were conducted between invasive and noninvasive somatotroph PitNETs. The expression of selected biomarkers was verified in PitNET tissue, and its correlation with various clinical indicators and outcomes of these tumours was assessed. The invasive phenotypes of GH3 cells were validated in vitro. RESULTS: Patients with invasive somatotroph PitNETs were significantly younger at onset and diagnosis, with significantly higher secretion and faster growth and a lower long-term biochemical response rate than patients with noninvasive somatotroph PitNETs. Proteomic data were evaluated in a consecutively collected sample of 19 (10 invasive and 9 noninvasive somatotroph PitNETs) tumours and indicated a distinct proteomic pattern. The enriched and important pathways included IL-4, PDGF, PTEN, VEGF, PI3K/AKT, FAK, and other pathways that were significantly associated with tumour proliferation, migration, and invasion. High cathepsin Z (CTSZ) expression was found in invasive somatotroph PitNETs and significantly positively correlated with parameters of tumour invasion and growth. In Ctsz-overexpressing GH3 cells, cell proliferation, invasion, and migration were consequently increased. CONCLUSION: It is more difficult for patients with invasive somatotroph PitNETs to achieve remission than those with noninvasive somatotroph PitNETs, and proteomic data analysis has revealed the high expression of CTSZ as a contributing factor to invasive transformation and poor prognosis in somatotroph PitNETs for the first time.

Serum metabolomics profiling of improved metabolic syndrome is characterized by decreased pro-inflammatory biomarkers: A longitudinal study in Chinese male adults.

Metabolic syndrome (MetS) is a serious global health concern. The objective of this study is to dynamically investigate the changes of metabolic profiles and metabolites in Chinese male MetS subjects after an 18 months diet and exercise intervention. Fifty male MetS patients defined according to International Diabetes Federation 2005 guidelines were subjected to diet and exercise counseling for 18 months. Serum samples were taken at baseline, 12 months, and 18 months, respectively, for clinical evaluation and metabolomics analyses. Diet and exercise intervention for 18 months achieved significant improvements in the metabolic profiles of all participants. Nineteen subjects (38.0%) exhibited MetS remission at the end of the study. A total of 812 relative features were characterized and 61 were successfully identified. Furthermore, 17 differential metabolites were of significance at both time points (baseline-12 months, baseline-18 months) and presented nonlinear trends through time. Eight metabolites (47.1%) were predominantly converged to inflammation and oxidative stress. Pro-inflammatory biomarkers were remarkably decreased after 18 months of intervention, and prostaglandin E2, neuroprotectin D1, and taxiphyllin in combination were firstly found to demonstrate a fair discriminative power (area under curve = 0.911) to predict the improvement of MetS undergone diet and exercise intervention. The significant shift of metabolomic profiling after 18 months of lifestyle counseling provide a novel insight and reveal that earlier inflammation control may be of potential benefit in MetS management.