Nanoscale octopus guiding telomere entanglement: An innovative strategy for inducing apoptosis in cancer cells.

Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.

Recent update on IGF-1/IGF-1R signaling axis as a promising therapeutic target for triple-negative breast cancer.

Insulin-like growth factor 1/Insulin-like growth factor 1-receptor (IGF-1/IGF-1R) pathway is highly breast cancer subtype context-dependent. Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic cancer showing early recurrence and poor prognosis. High expression of IGF-1 and its receptor IGF-1R, their interaction, autophosphorylation, and activation of intracellular signaling cascades have been significantly associated with TNBC pathophysiology. In the last five to seven years, marvelous work has been done to explore the role of IGF-1/IGF-1R axis in TNBC. In the present review, starting from the general introduction to IGF-1/IGF-1R pathway an up-to-date discussion was focused on its role in TNBC pathophysiology. Further we discussed the up/down stream molecular events of IGF-1/IGF-1R axis, clinical relevance of IGF-1 and IGF-1R levels in TNBC patients, anti-TNBC therapy and possible way-out for IGF-1/IGF-1R axis mediate therapy resistance in TNBC. Combination therapy strategy has been researched to overcome direct IGF-1/IGF-1R pathway inhibition mediated therapy resistance and produced promising results in the management of TNBC. The understanding of up/downstream of the IGF-1/IGF-1R axis provide immense focus on the pathway as a therapeutic target. It is expected within the next decade to determine its potentiality, or lack thereof, for TNBC treatment.

[Diagnosis and management of POEMS syndrome].

POEMS syndrome is a plasma cell neoplasm that presents with peripheral neuropathy, organomegaly, fluid retention, skin manifestations, osteosclerotic lesions, and λ-type M-proteinemia. The pathogenesis of POEMS syndrome is poorly understood, as the genetic profile of plasma cells in POEMS syndrome differs from that of myeloma. In most cases, POEMS syndrome is difficult to distinguish from chronic inflammatory demyelinating polyneuropathy (CIDP). Consequently, it is essential not to miss characteristic signs of POEMS syndrome such as M-protein, VEGF, pleural effusion, and osteosclerotic lesions. Novel agents for myeloma, such as thalidomide, lenalidomide, and bortezomib, are effective. For younger patients, these agents followed by autologous transplantation with high-dose melphalan is the standard of care. More relapses are now being reported in results of long-term observation, and treatment strategies for relapsed disease must be established.

Clinical evaluation of a multiplex PCR-based test for joint infection: a prospective diagnostic accuracy study of forty-nine patients.

PURPOSE: The purpose of this study was to evaluate the diagnostic accuracy (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) of the PCR-based BioFire® Joint Infection Panel (BJI Panel) against microbiological culture growth for patients suspected of having a native or prosthetic joint infection. METHODS: Synovial fluid and tissue biopsies were prospectively collected from patients from June 2022 to June 2023. The results of the BJI Panel were compared with those of culture growth. RESULTS: 51 samples were included. Including all pathogens, the sensitivity was 69%, the specificity 89%, the PPV 73% and the NPV 86%. Including only pathogens in the BJI Panel, the sensitivity was 100%, the specificity 90%, the PPV 73% and the NPV 100%. CONCLUSION: The BJI Panel has a high accuracy for detecting the pathogens in its panel, but the absence of important common pathogens from the panel reduces its sensitivity and NPV. With a short turnaround time and precise pathogen detection, the BJI Panel has the potential to add value as a complementary diagnostic method.

ETHYLENE RESPONSE FACTOR6, A Central Regulator of Plant Growth in Response to Stress.

ETHYLENE RESPONSE FACTOR6 (ERF6) has emerged as a central player in stress-induced plant growth inhibition. It orchestrates complex pathways that enable plants to acclimate and thrive in challenging environments. In response to various abiotic and biotic stresses, ERF6 is promptly activated through both ethylene-dependent and -independent pathways, and contributes to enhanced stress tolerance mechanisms by activating a broad spectrum of genes at various developmental stages. Despite the crucial role of ERF6, there is currently a lack of published comprehensive insights into its function in plant growth and stress response. In this respect, based on the tight connection between ethylene and ERF6, we review the latest research findings on how ethylene regulates stress responses and the mechanisms involved. In addition, we summarize the trends and advances in ERF6-mediated plant performance under optimal and stressful conditions. Finally, we also highlight key questions and suggest potential paths to unravel the ERF6 regulon in future research.

Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma.

PURPOSE: We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis. METHODS: We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated. RESULTS: TCERG1 expression was significantly higher in somatotroph adenomas than in normal pituitaries (log2 fold change 0.59, adjusted P = 0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P = 0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 3 (all P>0.05*). TCERG1 overexpression led to a 29.60% increase in proliferation (P<0.001*) and a 249.47% increase in invasion after 48 h in GH3 cells (P = 0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (25.76% at 72 h, P<0.001*) and invasion (96.87% at 48 h, P = 0.029*). E-cadherin was decreased, but vimentin was increased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. CONCLUSIONS: Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a biomarker for tumor aggressiveness.

Intravitreal faricimab for treatment naïve patients with neovascular age-related macular degeneration: a real-world prospective study.

BACKGROUND: Intravitreal faricimab, a bispecific antibody targeting both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), was recently introduced for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema and cystoid macular oedema secondary to retinal vein occlusion. The aim of our study was to assess the efficacy, safety and durability of intravitreal faricimab in a real-world cohort of treatment-naïve patients with nAMD. METHODS: Single-centre, prospective cohort study of 21 eyes from 19 treatment-naïve nAMD patients who were treated with intravitreal faricimab from October 2022 to April 2024. Patients underwent a loading dose (LD) of 4 monthly faricimab injections followed by a treat-and-extend regimen. Primary outcomes included best-corrected visual acuity (BCVA) and structural parameters from spectral-domain optical coherence tomography (SD-OCT). Secondary outcomes included the proportion of eyes achieving a dry macula, maximal fluid-free interval and intended interval at last follow-up. RESULTS: The study included 21 eyes of 19 patients (mean age 83.1 years). After LD, 93.3% of eyes achieved a dry macular SD-OCT scan within a median time of 8 weeks. At the first extension, 53% of eyes remained dry, while 47% showed fluid recurrence. Long-term analysis (n = 14) revealed significant reductions in macular volume (MV), central subfield thickness (CST), and pigment epithelial detachment (PED) height over a median follow-up of 64.9 weeks, with sustained visual and anatomical improvements. Median BCVA, CST, and MV at the final follow-up were significantly improved from baseline (p < 0.01). The intended interval between injections was ≥ 12 weeks in 42.86% of eyes. No cases of intraocular inflammation were observed, although 10% experienced retinal pigment epithelial tears. CONCLUSIONS: Intravitreal faricimab demonstrated favourable efficacy, safety, and durability outcomes in a real-world cohort of treatment-naïve nAMD patients.

Immunological correlates of suicidality among adolescents with internalizing symptoms.

Background: Suicide is a leading cause of death in adolescents and young adults globally. Well-established risk factors for suicide are depression and past suicide attempts. People experiencing suicidality may represent a distinct neurobiological group of people with depression. Because converging evidence has implicated inflammation in depression, we sought to investigate relationships between suicidality and immune markers in youth experiencing diverse mood and anxiety symptoms. We hypothesized that adolescents with suicidality would exhibit a unique immune signature. Methods: Adolescents underwent semi-structured interviews and completed self-reported measures to assess psychopathology, including suicidality (suicidal ideation, plans, or attempts). Fasting blood samples were collected, cultured with and without lipopolysaccharide (LPS) to stimulate an inflammatory response, and analyzed for 41 immune analytes. To assess how immune function related to suicidality categorically and dimensionally, we conducted group comparisons and correlations while controlling for multiple comparisons using false discovery rate (FDR). To further uncover subtle immune-suicidality relationships, we employed a data-driven approach using factor analysis to extract major immune factors, each of which was subsequently correlated with suicidality measures. Results: Among 126 participants, 29 were healthy controls and 97 participants had internalizing symptoms; within the clinical group, 57 experienced suicidality. Three immune analytes differed between healthy controls, suicidal, and non-suicidal adolescents with internalizing symptoms in the LPS condition: Flt-3L (p FDR = 0.0246), GM-CSF (p FDR = 0.0246), and IFN-γ (p FDR = 0.0246). These analytes were negatively correlated with the Beck Scale for Suicide Ideation (BSSI): Flt-3L (ρ = -0.19, p = 0.04); GM-CSF (ρ = -0.26, p = 0.004); IFN-γ (ρ =-0.33, p = 0.0003). GM-CSF also negatively correlated with number of suicide attempts (ρ = -0.39, p = 0.003). Factor analysis reduced 41 analytes to several common immune factors across experimental conditions, with Flt-3L, GM-CSF, and IFN-γ all loading heavily onto immune factors that were hypoactive in suicidality. Through this data-driven approach, we detected further associations between suicidality and immune factors across all conditions. Conclusions: Peripheral immune function may be distinctly altered in adolescent suicidality. Future work should examine immune-suicidality relationships longitudinally.

Successful cetuximab rechallenge in metastatic colorectal cancer: A case report.

BACKGROUND: Metastatic colorectal cancer (mCRC) treatment has been evolving and increasingly driven by tumor biology and gene expression analysis. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors (anti-EGFR) represents a promising strategy for patients with RAS wild-type (RAS-wt) mCRC and circulating tumor DNA has emerged as a potential selection strategy. Herein, we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge. CASE SUMMARY: Our patient was diagnosed with stage IV RAS-wt, microsatellite-stable rectosigmoid junction adenocarcinoma. He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response, allowing for a left hepatectomy (R0), followed by post-operative chemotherapy and an anterior resection; progression-free survival (PFS) of 16 months was obtained. Due to hepatic and nodal relapse, second-line treatment with FOLFOX and bevacizumab was started with partial response; metastasectomy was performed (R0), achieving a PFS of 11 months. After a 15 months anti-EGFR-free interval, FOLFIRI and cetuximab were reintroduced upon disease progression, again with partial response and a PFS of 16 months. Following extensive hepatic relapse, cetuximab was reintroduced and a marked clinical and analytical improvement was seen, after only one cycle. RAS-wt status was confirmed on circulating tumor DNA. The patient's overall survival exceeded 5 years. CONCLUSION: Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.

C23 ameliorates carbon tetrachloride-induced liver fibrosis in mice.

BACKGROUND: C23, an oligo-peptide derived from cold-inducible RNA-binding protein (CIRP), has been reported to inhibit tissue inflammation, apoptosis and fibrosis by binding to the CIRP receptor; however, there are few reports on its role in liver fibrosis and the underlying mechanism is unknown. AIM: To explore whether C23 plays a significant role in carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: CCl4 was injected for 6 weeks to induce liver fibrosis and C23 was used beginning in the second week. Masson and Sirius red staining were used to examine changes in fiber levels. Inflammatory factors in the liver were detected and changes in α-smooth muscle actin (α-SMA) and collagen I expression were detected via immunohistochemical staining to evaluate the activation of hematopoietic stellate cells (HSCs). Western blotting was used to detect the activation status of the transforming growth factor-beta (TGF-ß)/Smad3 axis after C23 treatment. RESULTS: CCl4 successfully induced liver fibrosis in mice, while tumor necrosis factor-alpha (TNF-α), IL (interleukin)-1ß, and IL-6 levels increased significantly and the IL-10 level decreased significantly. Interestingly, C23 inhibited this process. On the other hand, C23 significantly inhibited the activation of HSCs induced by CCl4, which inhibited the expression of α-SMA and the synthesis of collagen I. In terms of mechanism, C23 can block Smad3 phosphorylation significantly and inhibits TGF-ß/Smad3 pathway activation, thereby improving liver injury caused by CCl4. CONCLUSION: C23 may block TGF-ß/Smad3 axis activation, inhibit the expression of inflammatory factors, and inhibit the activation of HSCs induced by CCl4, alleviating liver fibrosis.

Diagnostic value of serum vascular endothelial growth factor and interleukin-17 in primary hepatocellular carcinoma.

BACKGROUND: Despite significant advancements in the medical treatment of primary hepatocellular carcinoma (PHC) in recent years, enhancing therapeutic effects and improving prognosis remain substantial challenges worldwide. AIM: To investigate the expression levels of serum vascular endothelial growth factor (VEGF) and interleukin (IL)-17 in patients with PHC and evaluate their diagnostic value while exploring their relationship with patients' clinical characteristics. METHODS: The study included 50 patients with confirmed PHC who visited Wuhan Hanyang Hospital from January 2021 to January 2022, and 50 healthy individuals from the same period served as the control group. Serum VEGF and IL-17 levels in both groups were measured by Enzyme-Linked Immunosorbent Assay, and their diagnostic value was assessed using receiver operating characteristic (ROC) curves. Pearson correlation analysis was performed to examine the relationship between serum VEGF and IL-17 levels. Pathological data of the PHC patients were analyzed to determine the relationship between serum VEGF and IL-17 levels and pathological characteristics. RESULTS: Serum VEGF and IL-17 levels were significantly higher in the study group compared to the control group (P < 0.05). No significant association was observed between serum VEGF and IL-17 levels and gender, age, combined cirrhosis, tumor diameter, or degree of differentiation (P > 0.05). However, there was a significant relationship between clinical TNM stage, tumor metastasis, and serum VEGF and IL-17 levels (P < 0.05). Correlation analysis revealed a positive correlation between serum VEGF and IL-17 (P < 0.05). ROC analysis demonstrated that both serum VEGF and IL-17 had good diagnostic efficacy for PHC. CONCLUSION: Serum VEGF and IL-17 levels were significantly higher in PHC patients compared to healthy individuals. Their levels were closely related to pathological features such as tumor metastasis and clinical TNM stage, and there was a significant positive correlation between VEGF and IL-17. These biomarkers may serve as valuable reference indicators for the early diagnosis and treatment guidance of PHC.

Inoculation with Jeotgalicoccus sp. improves nutritional quality and biological value of Eruca sativa by enhancing amino acid and phenolic metabolism and increasing mineral uptake, unsaturated fatty acids, vitamins, and antioxidants.

Plant growth-promoting bacteria (PGPB) are considered a promising tool for triggering the synthesis of bioactive compounds in plants and to produce healthy foods. This study aimed to demonstrate the impact of PGPB on the growth, accumulation of primary and secondary metabolites, biological activities, and nutritional qualities of Eruca sativa (arugula), a key leafy vegetable worldwide. To this end, Jeotgalicoccus sp. (JW0823), was isolated and identified by using partial 16S rDNA-based identification and phylogenetic analysis. The findings revealed that JW0823 significantly boosted plant biomass production by about 45% (P<0.05) and enhanced pigment contents by 47.5% to 83.8%. JW0823-treated plants showed remarkable improvements in their proximate composition and vitamin contents, with vitamin E levels increasing by 161.5%. JW0823 induced the accumulation of bioactive metabolites including antioxidants, vitamins, unsaturated fatty acids, and essential amino acids, thereby improving the nutritional qualities of treated plants. An increase in the amounts of amino acids was recorded, with isoleucine showing the highest increase of 270.2%. This was accompanied by increased activity of the key enzymes involved in amino acid biosynthesis, including glutamine synthase, dihydrodipicolinate synthase, cystathionine γ-synthase, and phenylalanine ammonia-lyase enzymes. Consequently, the total antioxidant and antidiabetic activities of the inoculated plants were enhanced. Additionally, JW0823 improved antimicrobial activity against several pathogenic microorganisms. Overall, the JW0823 treatment is a highly promising method for enhancing the health-promoting properties and biological characteristics of E. sativa, making it a valuable tool for improving the quality of this important leafy vegetable.

Clinical research progress of fruquintinib in the treatment of malignant tumors.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

Evaluation the Effects of Copper Nanoparticles Dietary Supplementation on Growth Performance, Carcass Characteristics, and Serum Antioxidant Status in Broilers.

The current study aims to assess the impact of different doses of feed supplementation of copper nanoparticles on broiler growth performance and carcass traits. The copper nanoparticles were synthesized by chemical reduction, and X-ray diffraction was used to characterize them. Iso-caloric and iso-nitrogenous starter and finisher basal diets were prepared and further supplemented with 0, 4, 8, and 12 mg/kg Cu nanoparticles for formulating T1, T2, T3 and T4 diets, respectively. A nearby hatchery provided 160-day-old broiler chicks, which were subsequently divided into 4 groups at random. There were 4 repetitions of each treatment, with 10 birds in each replication. Results revealed that average weight and FCR were improved in birds fed feed containing 12 mg nano Cu when compared to other groups. Feed intake, carcass characteristics, and dry matter and crude protein metabolizability were not influenced by different levels of Cu nanoparticles, while the metabolizability of crude fat was significantly higher (P < 0.05) in T4 compared among all treatment groups. Catalase concentration was higher (p < 0.05) in T3 and T4 compared to other treatments, while the concentration of superoxide dismutase was high in T2 and T4. The water-holding capacity of meat was significantly higher (P < 0.05) in T4. The findings of the present study concluded that dietary supplementation of Cu nanoparticles at 12 mg/kg feed can be practiced to get better broiler performance. According to the current study's findings, broiler performance can be improved by supplementing the food with 12 mg/kg of Cu nanoparticles.

Maternal Mediterranean Diet During Lactation and Infant Growth.

Background: Human milk is considered the optimal source of nutrition for infants. Maternal diet is associated with the composition of human milk. The Mediterranean diet (MedDiet) has been studied in pregnancy and during lactation, and it has been associated with changes in milk composition, yet there is a lack of research on MedDiet during lactation and infant outcomes. Methods: Mother-infant dyads (n = 167) from ABC Baby, a prospective observational study, were included in this analysis. Maternal diet was obtained using an adapted version of the National Cancer Institute Diet History Questionnaire II, at 2 weeks or 2 months postpartum. Maternal MedDiet score was calculated using servings of vegetables, fruits, whole grains, nuts and seeds, legumes, fish, monounsaturated-to-saturated fatty acid ratio, red and processed meats, and added sugar. Infants' length, weight, and flank skinfold thickness were measured at 6 months. Using World Health Organization standards, weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) Z-scores were calculated. Multiple linear regression models were adjusted for potential confounders. Results: Higher maternal MedDiet score and intake of fruit and fish were associated with lower flank skinfold thickness (ß = -0.33, -0.52, and -1.26, respectively). Intake of nuts and seeds was associated with higher WLZ (ß = 0.29). Intake of red and processed meats was associated with lower WAZ (ß = -0.18) and LAZ (ß = -0.18). Energy-adjusted added sugar intake was associated with lower WLZ (ß = -0.02). Conclusions: The maternal MedDiet score was associated with lower skinfold thickness, while its components were associated with differences in anthropometric Z-scores. Further research on the maternal MedDiet and corresponding human milk composition is needed to explore this relationship.

Development of new sustainable pyridinium ionic liquids: From reactivity studies to mechanism-based activity predictions.

CONTEXT: This study addresses the development of sustainable pyridinium ionic liquids (ILs) because of their potential applications in agriculture and pharmaceuticals. Pyridinium-based ILs are known for their low melting points, high thermal stability, and moderate solvation properties. We synthesized three novel pyridinium-based ILs: 1-(2-(isopentyloxy)-2-oxoethyl)pyridin-1-ium chloride, 1-(2-(hexyloxy)-2-oxoethyl)pyridin-1-ium chloride, and 1-(2-(benzyloxy)-2-oxoethyl)pyridin-1-ium chloride. The biological activities of these compounds were evaluated through plant growth promotion, herbicidal, and insecticidal assays. Our results show that the benzyloxy derivative significantly enhances wheat and cucumber growth, whereas the isopentyloxy compound has potent herbicidal effects. Computational methods, including DFT calculations and molecular docking, were applied to understand the structure‒activity relationships (SARs) and mechanisms of action. METHODS: The computational techniques involved dispersion-corrected density functional theory (DFT) with the B3LYP functional and the 6-311G** basis set. Grimme's D3 corrections were included to account for dispersion interactions. The calculations were performed via GAMESS-US software. Quantum descriptors of reactivity, such as ionization potential, electron affinity, chemical potential, and electrophilicity index, were derived from the HOMO and LUMO energies. Molecular docking studies were conducted via the CB-Dock server via AutoDock Vina software to predict binding affinities to cancer-related proteins. Petra/Osiris/Molinspiration (POM) analysis was used to predict the drug likeness and other pharmaceutical properties of the synthesized ILs.

The influence of genotype makeup on the effectiveness of growth hormone therapy in children with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS. METHODS: A review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment. RESULTS: Children with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05). CONCLUSIONS: rhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.

Increased vascular endothelial growth factor expression is associated with cruciate ligament degeneration in patients with osteoarthritis of the knee.

BACKGROUND: This study aimed to investigate the expression of vascular endothelial growth factor (VEGF) in cruciate ligaments from patients with osteoarthritis (OA). It was hypothesized that the expression level of VEGF is associated with the extent of degeneration of the cruciate ligaments. METHODS: Remnants of anterior cruciate ligaments (ACLs) from patients with acute ACL injury due to trauma, and ACLs and posterior cruciate ligaments (PCLs) from patients with primary OA were assessed histologically. Samples were immunohistochemically stained with VEGF and tenomodulin, and immunopositive cells were quantitatively assessed by the histological grades of ligament degeneration. RESULTS: Histological analysis showed significant degeneration of the ACLs from OA patients compared with trauma patients, with increased expression of VEGF correlating with higher grades of degeneration. Conversely, tenomodulin expression was lower in more degenerated cruciate ligaments. The percentage of VEGF-positive cells was correlated inversely with that of tenomodulin-positive cells. CONCLUSIONS: Increased VEGF expression is associated with degeneration of cruciate ligaments in patients with osteoarthritis of the knee.

Association of brown adipose tissue activity with circulating sex hormones and fibroblast growth factor 21 in the follicular and luteal phases in young women.

BACKGROUND: Thermogenesis is influenced by fluctuations in sex hormones during the menstrual cycle in premenopausal women. The thermogenic activity and mass of brown adipose tissue (BAT) are regulated by endocrine factors, including sex hormones and fibroblast growth factor 21 (FGF21). However, the relationship between human BAT and these endocrine fluctuations within individuals remains to be elucidated. This study aimed to assess variations in BAT activity between the luteal and follicular phases and identify correlations with circulating levels of sex hormones and FGF21. METHODS: Healthy young women were enrolled in an observational study. Measurement of BAT activity and blood analyses were performed in both the follicular and luteal phases. BAT activity was analyzed using thermography with 2-h cold exposure. Plasma 17ß-estradiol, progesterone, and FGF21 levels were determined by enzyme-linked immunosorbent assay. A comparative analysis within individuals was conducted in 13 women to compare the follicular and luteal phases. Furthermore, sensitivity analysis was carried out in 21 women during the follicular phase only. RESULTS: Plasma 17ß-estradiol and progesterone levels were significantly higher in the luteal phase, whereas plasma FGF21 level was significantly higher in the follicular phase. Comparison analysis found no significant differences in cold-induced BAT activity between the follicular and luteal phases in young women. Correlation analysis in both comparison and sensitivity analyses found that plasma 17ß-estradiol and progesterone levels were not associated with BAT activity, whereas plasma FGF21 levels were significantly and positively correlated with BAT activity only in the follicular phase. In addition, plasma 17ß-estradiol levels in the follicular phase were significantly and positively associated with plasma FGF21 levels in both the comparison and sensitivity analyses. CONCLUSIONS: The thermogenic activity of BAT during cold exposure was comparable between the follicular and luteal phases in young women. Higher BAT activity was associated with elevated levels of plasma FGF21 only in the follicular phase, which is related to increased plasma 17ß-estradiol levels.

Effects of letrozole on rat placental development.

We examined the morphological effects of letrozole on placental development in pregnant rats. Letrozole was orally administered at a repeat dose to pregnant rats at 0 mg/kg (control group) and 0.04 mg/kg (letrozole group) from gestation day (GD) 6 to GD 20. In the letrozole group, fetal mortality and placental weight increased from GD 15 onwards and GD 13 onwards, respectively. Fetal weights increased on GDs 15 and 17 but decreased on GD 21. Histopathologically, letrozole treatment induced multiple cysts lined with undifferentiated syncytiotrophoblasts in the trophoblastic septa on GD 13. These cysts then develop into dilated maternal sinusoids with congestive hyperemia, resulting in an enlarged placenta. In the metrial gland, there was a dilated lumen of the spiral artery and interstitial edema throughout the experimental period, resulting in thickened metrial gland. These changes are considered to be due to maternal blood circulation stagnation in the metrial gland, which is associated with dilated maternal sinusoids in the labyrinth zone. Thus, although letrozole induces an enlarged placenta due to congestive hyperemia of the labyrinth zone and transient increases in fetal weight, these placentas are thought to decline in function as the pregnancy progresses, leading to intrauterine growth restriction at the end of pregnancy.