Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL.

PURPOSE: At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. METHODS: In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. RESULTS: Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. CONCLUSION: Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

Magnetic Dipole Transition in

The magnetic dipole transition strength B(M1) of ^{48}Ca is dominated by a single resonant state at an excitation energy of 10.23 MeV. Experiments disagree about B(M1) and this impacts our understanding of spin flips in nuclei. We performed ab initio computations based on chiral effective field theory and found that B(M1: 0^{+}→1^{+}) lies in the range from 7.0 to 10.2 µ_{N}^{2}. This is consistent with a (γ,n) experiment but larger than results from (e,e^{'}) and (p,p^{'}) scattering. Two-body currents yield no quenching of the B(M1) strength and continuum effects reduce it by about 10%. For a validation of our approach, we computed magnetic moments in ^{47,49}Ca and performed benchmark calculations in light nuclei.

Preoperative BMI and Hb levels are important predictors of massive bleeding in liver transplant patients.

OBJECTIVE: This study aims to compare intraoperative bleeding during liver transplant procedures and analyze the predictive role of preoperative laboratory indicators in significant intraoperative bleeding. PATIENTS AND METHODS: A retrospective analysis was conducted on 271 cases of allogeneic liver transplant patients from January 2018 to June 2023. Patients were categorized into the massive bleeding (MB) group and the non-massive bleeding (non-MB) group based on the occurrence of significant intraoperative bleeding. Preoperative laboratory parameters between the MB and non-MB groups were compared, and univariate and multivariate regression analyses were performed. ROC curves were performed to analyze the value of these parameters in distinguishing the MB and non-MB groups. RESULTS: In the MB group, body mass index (BMI), hemoglobin (Hb), platelet count (PLT), fibrinogen (Fib), and total protein (TP) levels were significantly lower than those in the non-MB group (p < 0.05). Conversely, prothrombin time (PT), international normalized ratio (INR), total bilirubin (TBIL), creatinine (CRE), blood urea nitrogen (BUN), the model for end-stage liver disease (MELD) score, length of stay, and hospital stay were significantly higher in the MB group compared to the non-MB group (p < 0.05). Univariate and multivariate logistic regression analyses revealed that preoperative BMI and Hb were independent risk factors for massive bleeding during liver transplantation. ROC curve analysis for predicting massive intraoperative bleeding showed that the area under the curve (AUC) of Hb was considerable (AUC: 0.83). CONCLUSIONS: Preoperative BMI and Hb levels are critical predictors of massive bleeding during liver transplantation, emphasizing the importance of proactive management based on these indicators for improved patient outcomes.

[Efficacy evaluation of 0.05% cyclosporine A and 0.1% tacrolimus eye drops in the treatment of severe dry eye associated with chronic graft-versus-host disease].

Objective: To evaluate the effectiveness and safety of 0.05% cyclosporine A and 0.1% tacrolimus eye drops in treating severe dry eye associated with chronic graft-versus-host disease (cGVHD). Methods: This non-randomized concurrent control trial enrolled 83 eyes from 83 patients with cGVHD-associated severe dry eye. The treatment had two phases. During the initial shock treatment period (0-3 months), 44 patients received 0.05% cyclosporine A eye drops (4 times/day; group A) and 39 patients received 0.1% tacrolimus eye drops (twice/day; group B) alongside basic treatment. In the maintenance treatment period (3-6 months), both groups used 0.05% cyclosporine A eye drops (twice/day) and sodium hyaluronate. Examinations were conducted at 1, 3, and 6 months after treatment initiation, assessing the Ocular Surface Disease Index (OSDI), corneal fluorescein staining (CFS) score, and fluorescein tear break-up time (BUT) for efficacy. visual acuity and intraocular pressure (IOP) were evaluated for safety, and patients' post-medication irritation symptoms were recorded. Results: The study included 52 males and 31 females, aged (28.57±15.67) years. After 1 month of treatment, the CFS score in group A significantly decreased from 10.0 (6.0, 14.0) to 5.0 (3.0, 8.5) (P<0.001). in group B, the CFS score also significantly decreased from 10.0 (6.0, 15.0) to 6.0 (2.0, 10.0), and the BUT increased from 2.0 (1.0, 2.0) s to 2.0 (1.8, 3.3) s (P<0.001). No significant OSDI decrease was observed in either group. No significant differences were found in OSDI, CFS score, and BUT between the two groups. After 3 months, group A showed significant improvement in OSDI, CFS score, and BUT (P<0.05), while group B only demonstrated significant CFS score decrease (P<0.05). OSDI was significantly lower in group A than group B (P<0.05). No significant differences were noted in CFS score and BUT between groups. After 6 months, OSDI, CFS score, and BUT were 18.9 (9.3, 34.2), 7.0 (3.0, 8.5), and 2.0 (1.0, 3.0) s in group A, and 10.9 (3.6, 35.4), 5.5 (2.8, 10.0), and 2.0 (1.0, 10.0) s in group B. In both groups, CFS scores significantly decreased and BUT increased (P<0.05). Visual acuity improved significantly in group A at 1, 3, and 6 months (P<0.05), while no significant changes were seen in group B. Irritation symptoms were transient and self-resolving in both groups. Conclusions: Both 0.05% cyclosporine A and 0.1% tacrolimus eye drops, when combined with local glucocorticoids, exhibited significant anti-inflammatory effects, effectively and safely treating severe dry eye in cGVHD patients. Although the onset of 0.05% cyclosporine A was slower than 0.1% tacrolimus, it offered more stable long-term effects and better symptom improvement.

Isomeric Excitation Energy for

The excitation energy of the 1/2^{-} isomer in ^{99}In at N=50 is measured to be 671(37) keV and the mass uncertainty of the 9/2^{+} ground state is significantly reduced using the ISOLTRAP mass spectrometer at ISOLDE/CERN. The measurements exploit a major improvement in the resolution of the multireflection time-of-flight mass spectrometer. The results reveal an intriguing constancy of the 1/2^{-} isomer excitation energies in neutron-deficient indium that persists down to the N=50 shell closure, even when all neutrons are removed from the valence shell. This trend is used to test large-scale shell model, ab initio, and density functional theory calculations. The models have difficulties describing both the isomer excitation energies and ground-state electromagnetic moments along the indium chain.

Improved Measurement of the Evolution of the Reactor Antineutrino Flux and Spectrum at Daya Bay.

Reactor neutrino experiments play a crucial role in advancing our knowledge of neutrinos. In this Letter, the evolution of the flux and spectrum as a function of the reactor isotopic content is reported in terms of the inverse-beta-decay yield at Daya Bay with 1958 days of data and improved systematic uncertainties. These measurements are compared with two signature model predictions: the Huber-Mueller model based on the conversion method and the SM2018 model based on the summation method. The measured average flux and spectrum, as well as the flux evolution with the ^{239}Pu isotopic fraction, are inconsistent with the predictions of the Huber-Mueller model. In contrast, the SM2018 model is shown to agree with the average flux and its evolution but fails to describe the energy spectrum. Altering the predicted inverse-beta-decay spectrum from ^{239}Pu fission does not improve the agreement with the measurement for either model. The models can be brought into better agreement with the measurements if either the predicted spectrum due to ^{235}U fission is changed or the predicted ^{235}U, ^{238}U, ^{239}Pu, and ^{241}Pu spectra are changed in equal measure.

Efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder.

OBJECTIVE: The current research was designed to assess the efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder. PATIENTS AND METHODS: A total of 154 children with tic disorder co-morbid with attention deficit hyperactivity disorder admitted to our hospital from July 2019 to July 2022 were recruited and assigned to receive either methylphenidate hydrochloride plus haloperidol (observation group) or clonidine (experimental group), with 77 cases in each group. Outcome measures included clinical efficacy, Yale Global Tic Severity Scale (YGTSS) scores, Conners Parent Symptom Questionnaire (PSQ) scores, and adverse events. RESULTS: Clonidine was associated with markedly higher clinical efficacy vs. methylphenidate hydrochloride plus haloperidol (p<0.05). Clonidine offered more significant mitigation of the tic disorder vs. methylphenidate hydrochloride plus haloperidol, as evinced by the lower kinetic tic scores, vocal tic scores, and total scores (p<0.05). Children exhibited markedly milder tic symptoms after clonidine monotherapy vs. those with dual therapy of methylphenidate hydrochloride and haloperidol, suggested by the lower scores of character problems, learning problems, psychosomatic disorders, hyperactivity/impulsivity, anxiety index, and hyperactivity index (p<0.05). Clonidine features a higher safety profile than methylphenidate hydrochloride plus haloperidol by reducing the incidence of adverse events (p<0.05). CONCLUSIONS: Clonidine effectively alleviates tic symptoms, reduces attention deficit and hyperactivity/impulsivity in children with tic disorder co-morbid attention deficit hyperactivity disorder, and features a high safety profile.

Mass spectrometry-based metabolic profiling for identification of biomarkers related to footpad dermatitis in ducks.

1. A new assessment method for duck footpad dermatitis (FPD) evaluation was developed, combining visual and histological characters using the images and sections of 400 ducks' feet at 340 d of age. All ducks were graded as G0 (healthy), G1 (mild), G2 (moderate) and G3 (severe) according to the degree of FPD.2. To reveal the potential biomarkers in serum related to duck FPD, non-targeted metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore differential metabolites in each group.3. There were 57, 91 and 210 annotated differential metabolites in groups G1, G2 and G3 compared with G0, which meant that the severity of FPD increased in line with the number of metabolites. Four metabolites, L-phenylalanine, L-arginine, L-leucine and L-lysine, were considered potential biomarkers related to FPD.4. KEGG enrichment analysis showed that the FPD was mainly involved in glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway and amino acid metabolism. These are related to production metabolism and can affect the physiological activities of ducks, which might explain the decrease in production performance.

Precision Measurement of Reactor Antineutrino Oscillation at Kilometer-Scale Baselines by Daya Bay.

We present a new determination of the smallest neutrino mixing angle θ_{13} and the mass-squared difference Δm_{32}^{2} using a final sample of 5.55×10^{6} inverse beta-decay (IBD) candidates with the final-state neutron captured on gadolinium. This sample is selected from the complete dataset obtained by the Daya Bay reactor neutrino experiment in 3158 days of operation. Compared to the previous Daya Bay results, selection of IBD candidates has been optimized, energy calibration refined, and treatment of backgrounds further improved. The resulting oscillation parameters are sin^{2}2θ_{13}=0.0851±0.0024, Δm_{32}^{2}=(2.466±0.060)×10^{-3} eV^{2} for the normal mass ordering or Δm_{32}^{2}=-(2.571±0.060)×10^{-3} eV^{2} for the inverted mass ordering.

[Two cases of airway dysfunction related to diacetyl exposure].

Occupational exposure to diacetyl can lead to bronchiolitis obliterans. In this paper, two patients with severe obstructive ventilation disorder who were exposed to diacetyl at a fragrance and flavours factory were analyzed. The clinical manifestations were cough and shortness of breath. One of them showed Mosaic shadows and uneven perfusion in both lungs on CT, while the other was normal. Field investigation found that 4 of the 8 workers in the factory were found to have obstructive ventilation disorder, and 2 had small airway dysfunction. This paper summarizes the diagnostic process of patients in order to improve the understanding of airway dysfunction caused by occupational exposure to diacetyl and promote the development of relevant standards.

CircOMA1 modulates cabergoline resistance by downregulating ferroptosis in prolactinoma.

PURPOSE: Prolactinomas are one of the most common pituitary neuroendocrine tumors (PitNETs), accounting for approximately 50% of all pituitary tumors. Dopamine agonists are the main treatment for prolactinoma, but a small number of patients are still resistant to pharmacotherapy. Recent discoveries have revealed that ferroptosis is involved in regulating tumor drug resistance. However, the role of ferroptosis in prolactinoma has not been reported. In this study, we aimed to explore the mechanism of a circRNA in ferroptosis in prolactinoma. METHODS: The expression of circOMA1 in prolactinoma tissues was examined by quantitative reverse transcription PCR (qRT-PCR). The biological function of circOMA1 was evaluated in vitro and in vivo. To explore the role of ferroptosis in prolactinoma, we used qRT-PCR and western blotting. Glutamate-cysteine ligase, modifier subunit (GCLM) was predicted to be a direct target gene of miR-145-5p by bioinformatics analysis, which was confirmed by luciferase reporter assays. RESULTS: circOMA1 was overexpressed in drug-resistant prolactinoma tissues compared with sensitive prolactinoma samples. We further found that circOMA1 promoted MMQ cells growth in vivo and in vitro. In addition, GCLM was directly targeted by miR-145-5p and indirectly regulated by circOMA1. Importantly, circOMA1 induced ferroptosis resistance through the increased expression of Nrf2, GPX4, and xCT, and circOMA1 attenuated CAB-induced ferroptosis in MMQ cells in vivo and in vitro. CONCLUSION: The present study demonstrates that circOMA1 attenuates CAB efficacy through ferroptosis resistance and may be a new therapeutic target for the individualized treatment of DA-resistant prolactinoma patients.

Transmutation of MAs and LLFPs with a lead-cooled fast reactor.

The management of nuclear wastes has long been a problem that hinders the sustainable and clean utilization of nuclear energy since the advent of nuclear power. These nuclear wastes include minor actinides (MAs: 237Np, 241Am, 243Am, 244Cm and 245Cm) and long-lived fission products (LLFPs: 79Se, 93Zr, 99Tc, 107Pd, 129I and 135Cs), and yet are hard to be handled. In this work, we propose a scheme that can transmute almost all the MAs and LLFPs with a lead-cooled fast reactor (LFR). In this scheme, the MAs and the LLFPs are loaded to the fuel assembly and the blanket assembly for transmutation, respectively. In order to study the effect of MAs loading on the operation of the core, the neutron flux distribution, spectra, and the keff are further compared with and without MAs loading. Then the LLFPs composition is optimized and the support ratio is obtained to be 1.22 for 237Np, 1.63 for 241Am, 1.27 for 243Am, 1.32 for 79Se, 1.53 for 99Tc, 1.02 for 107Pd, and 1.12 for 129I, respectively, indicating that a self-sustained transmutation can be achieved. Accordingly, the transmutation rate of these nuclides was 13.07%/y for 237Np, 15.18%/y for 241Am, 13.34%/y for 243Am, 0.58%/y for 79Se, 0.92%/y for 99Tc, 1.17%/y for 107Pd, 0.56%/y for 129I. Our results show that a lead-cooled fast reactor can be potentially used to manage nuclear wastes with high levels of long-lived radioactivity.

Predictors of postoperative biochemical remission in lower Knosp grade growth hormone-secreting pituitary adenomas: a large single center study.

PURPOSE: Growth hormone-secreting pituitary adenomas (GH-PAs) with a low Knosp grade are typically associated with a good postoperative biochemical remission (BR) rate. However, a proportion of patients do not achieve remission. In this study, we aimed to investigate predictive factors of postoperative remission for lower Knosp GH-PAs. METHODS: In this retrospective study, we enrolled 140 patients who were diagnosed with lower Knosp (0-2) GH-PAs and received trans-sphenoidal surgery between December 2016 and June 2021 from the largest pituitary tumor surgery center in southern China. The univariate, binary Logistic regression, and receiver operating characteristic curve (ROC) analyses were employed to determine independent predictors and cutoff values of remission. The postoperative outcome was defined as remission using the 2010 consensus criteria of acromegaly. RESULTS: One hundred and thirty six patients (97.1%) achieved gross total resection. The postoperative long-term BR was 68.6%. Empty sella, tumor maximum diameter and postoperative GH levels were independent factors predicting remission. ROC revealed that postoperative 24 h GH ≤ 1.3 ng/mL and ≤ 1.23 ng/mL were valuable predictors for 3-month and long-term remission respectively, and that postoperative 3-month GH ≤ 1.6 ng/mL and tumor maximum diameter ≤ 17 mm were predictors for delayed remission. CONCLUSION: Early postoperative GH levels can be used as predictors of remission. However, BR was not associated with preoperative somatostatin analogs therapy or Knosp grade (0-2). For patients without residual tumor or recurrence and whose GH levels are slightly elevated within 1 year after surgery, adjuvant treatments may not be necessary.

Observation of the Exotic 0_{2}

We report here the first observation of the 0_{2}^{+} state of ^{8}He, which has been predicted to feature the condensatelike α+^{2}n+^{2}n cluster structure. We show that this state is characterized by a spin parity of 0^{+}, a large isoscalar monopole transition strength, and the emission of a strongly correlated neutron pair, in line with theoretical predictions. Our finding is further supported by the state-of-the-art microscopic α+4n model calculations. The present results may lead to new insights into clustering in neutron-rich nuclear systems and the pair correlation and condensation in quantum many-body systems under strong interactions.

[Associations between 24-hour urinary sodium excretion and all-cause mortality in adults living in north China].

Objective: To investigate the associations between 24-hour urinary sodium excretion (24hUNaE) and all-cause mortality in adult Northern Chinese population. Methods: Data from this study were derived from the prospective urban and rural epidemiology (PURE) study in north China. Baseline information of all participants were obtained by face to face interview through trained research staffs based on questionnaires, and morning fasting urine samples of participants were collected to estimate 24hUNaE and 24-hour potassium excretion (24hUKE). Multivariable frailty Cox regression models were used to explore the association between 24hUNaE (<3.00, 3.00-3.99, 4.00-4.99, 5.00-5.99 and ≥6 g/d) and all-cause death. Results: A total of 27 310 participants were included in this study. The mean 24hUNaE was (5.84±1.73) g/d. After a median follow-up of 8.8 years, 1 024 participants died (3.7%), including 390 cardiovascular related deaths and 591 non-cardiovascular related deaths. The cause of death of the remaining patients could not be determined. Using 24hUNaE level of 4.00-4.99 g/d as the reference group, after fully adjustment, 24hUNaE ≥6.00 g/d was associated with an increased risk of all-cause death (HR=1.24, 95%CI: 1.02-1.49) and cardiovascular related death (HR=1.39, 95%CI: 1.02-1.88). 24hUNaE<3.00 g/d was associated with increased risk of all-cause mortality (HR=1.38, 95%CI: 0.96-1.99). There was no significant association between 24hUNaE and non-cardiovascular related death. Furthermore, using the combination of 24hUNaE 4.00-4.99 g/d and 24hUKE≥2.11 g/d as the reference group, the highest risk occurred in participants with the combination of low sodium (<3.00 g/d) and low potassium (<2.11 g/d). Conclusion: 24hUNaE equal or higher than 6 g/d or lower than 3 g/d is associated with increased risk of all-cause mortality and cardiovascular related death in Northern Chinese population. Besides, moderate sodium intake in combination with increased potassium intake might reduce the risk of all-cause death.

Repurposing Ivermectin to augment chemotherapy's efficacy in osteosarcoma.

BACKGROUND: Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have anti-cancer activity. This work investigated the potential of repurposing ivermectin to augment chemotherapy's efficacy in osteosarcoma. METHODS: Proliferation, migration and apoptosis assays were performed in ivermectin-treated osteosarcoma cells. Combination studies were performed. Osteosarcoma xenograft mouse model was established to investigate the in vivo efficacy of ivermectin. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide, membrane potential, ATP, 8-OHdG level, protein carbonylation and lipid peroxidation were determined after ivermectin treatment. RESULTS: Ivermectin was effective and acted synergistically with doxorubicin in osteosarcoma cells regardless of cellular origin and genetic profiling. This was achieved through suppressing inhibiting growth and migration, and inducing caspase-dependent apoptosis. Ivermectin also significantly inhibited osteosarcoma growth in vivo and its combination with doxorubicin resulted in much greater efficacy than doxorubicin alone. Importantly, the effective dose of ivermectin was clinically feasible and did not cause significant toxicity in mice. Mechanistical analysis showed that ivermectin induced oxidative stress and damage, and mitochondrial dysfunction. CONCLUSIONS: Our findings indicate that ivermectin has utility in treating patients with osteosarcoma, especially those resistant to chemotherapy.

[Comparison of psychological distress and quality of life in patients with advanced liver cancer before and after transformation therapy].

OBJECTIVE: To analyze the changes in psychological distress and quality of life of patients with advanced liver cancer after transformation therapy. METHODS: This study was conducted among 60 patients with advanced liver cancer undergoing transformation therapy from July, 2019 to March, 2022. Before and after 2-10 cycles of treatment, the patients were assessed for psychological distress and quality of life using a psychological stress thermometer and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep). RESULTS: The patients showed significantly lowered scores for psychological distress after transformation therapy (P < 0.01) with decreased psychological stress, emotional factors, tension, worry, sleep problems, memory decline and inattention, physical factors, pain, fatigue, eating problems and dyspepsia (P < 0.05). The total score of quality of life and the scores for physical status, social and family status, emotional status, functional status and hepatobiliary-specific items were all significantly lowered after the treatment (P < 0.05). CONCLUSION: In patients with advanced liver cancer, the psychological distress involves mainly the emotional factors and physical factors. Transformation therapy can significantly relieve psychological distress of the patients and improve their quality of life.