Glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome: Two sides of the same coin.

Diseases of the adrenal glands can lead to primary adrenal insufficiency, and suppression of the hypothalamic-pituitary-adrenal axis can cause secondary adrenal insufficiency (adrenal suppression). The most common cause of adrenal suppression is exogenous steroids, a condition recently termed glucocorticoid-induced adrenal insufficiency (GIAI). Similarly, weaning from high doses of glucocorticoids or giving insufficient glucocorticoid replacement after curative surgery for endogenous hypercortisolism (Cushing syndrome) can lead to glucocorticoid withdrawal syndrome, which overlaps with GIAI.

Risk of dementia and psychiatric or sleep disorders after diagnosis of adrenal adenomas: a population-based cohort study.

OBJECTIVE: Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. DESIGN: Population-based cohort study, Olmsted County, MN, 1995-2017. METHODS: Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. RESULTS: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. CONCLUSIONS: Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

Glucocorticoid withdrawal syndrome following surgical remission of endogenous hypercortisolism: a longitudinal observational study.

OBJECTIVE: Glucocorticoid withdrawal syndrome (GWS) is a scarcely studied phenomenon that complicates the recovery following surgical remission of hypercortisolism. We aimed to characterize the presence and trajectory of glucocorticoid withdrawal symptoms in the postoperative period and to determine presurgical predictors of GWS severity. DESIGN: Longitudinal observational study. METHODS: Glucocorticoid withdrawal symptoms were prospectively evaluated weekly for the first 12 weeks following surgical remission of hypercortisolism. Quality of life (CushingQoL and Short-Form-36) and muscle function (hand grip strength and sit-to-stand test) were assessed at the baseline and at 12 weeks after surgery. RESULTS: Prevalent symptoms were myalgias and arthralgias (50%), fatigue (45%), weakness (34%), sleep disturbance (29%), and mood changes (19%). Most symptoms persisted, while myalgias, arthralgias, and weakness worsened during weeks 5-12 postoperatively. At 12 weeks after surgery, normative hand grip strength was weaker than at baseline (mean Z-score delta -0.37, P = .009), while normative sit-to-stand test performance improved (mean Z-score delta 0.50, P = .013). Short-Form-36 Physical Component Summary score worsened (mean delta -2.6, P = .015), but CushingQoL score improved (mean delta 7.8, P < .001) at 12 weeks compared to baseline. Cushing syndrome (CS) clinical severity was predictive of postoperative GWS symptomology. CONCLUSION: Glucocorticoid withdrawal symptoms are prevalent and persistent following surgical remission of hypercortisolism with baseline CS clinical severity predictive of postoperative GWS symptom burden. Differential changes observed in muscle function and quality of life in the early postoperative period may reflect the competing influences of GWS and recovery from hypercortisolism.

The landscape of aging.

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Background: Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. Methods: We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. Results: As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Conclusions: Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Biochemical assessment of adrenal insufficiency after adrenalectomy for non-cortisol secreting tumors: clinical correlation and recommendations.

BACKGROUND: Data regarding changes in cortisol axis after adrenalectomy for non-cortisol secreting tumors and their correlation with adrenal insufficiency are limited. Our aim was to analyze these changes and their clinical correlations to guide management after adrenalectomy for non-Cushing's tumors. METHODS: Following IRB approval, postoperative cortisol axis changes were analyzed in patients who underwent unilateral adrenalectomy for non-Cushing's tumors. A morning serum cortisol of ≥ 10 µg/dl was accepted as a sufficient adrenal response. RESULTS: 223 adrenalectomies were analyzed. In 63% of patients, POD1 serum cortisol was ≥ 10 µg/dl and in 37% < 10 µg/dl. No patient with a POD1 cortisol ≥ 10 µg/dl developed AI symptoms, whereas symptoms of AI were observed in 4% of those with < 10 µg/dl. In patients with a POD1 cortisol of < 10 µg/dl, the rate of steroid replacement therapy initiation was 100%, 8%, and 25% when the decision was based on serum cortisol, clinical symptoms, and serum cortisol plus ACTH stimulation test results, respectively. In 90% of asymptomatic patients, hypocortisolemia resolved uneventfully within a week on repeat morning cortisol testing. 75% of patients with hypocortisolemia on POD1 demonstrated an adequate cortisol response to ACTH stimulation test. CONCLUSION: Although postoperative hypocortisolemia was observed in 37% of patients undergoing unilateral adrenalectomy for non-cortisol secreting tumors, majority did not develop symptoms of adrenal insufficiency. All three steroid initiation approaches appeared safe, with management based on clinical symptoms or selective ACTH stimulation testing sparing more patients from steroids compared to steroid initiation based on POD 1 cortisol levels alone.

Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PNDs) are a type of cognitive dysfunction occurring with a higher incidence in elderly patients. However, the pathological mechanism of PND and effective treatment remain elusive. We generated a PND mouse model by providing wild-type mice with surgical trauma; in our case, we used tibial fracture to investigate PND pathology. Mice aged 7-8 months were randomly divided into two groups: the surgery (tibial fracture) group and the control (sham) group. All mice were subjected to anesthesia. We examined the transcriptome-wide response in the hippocampus, a brain region that is tightly associated with memory formation, of control mice and mice subjected to surgical trauma at day 1 and day 3 after the surgical procedure. We observed reduced transcript levels of respiratory complex components as early as day 1 after surgery, and subsequent protein changes were found at day 3 after surgical trauma. Consequently, the activities of respiratory complexes were reduced, and adenosine triphosphate (ATP) production was decreased in the hippocampus of mice with surgical operations, supporting that respiratory chain function was impaired. In support of these conclusions, the mitochondrial membrane potential (MMP) levels were decreased, and the reactive oxygen species (ROS) levels were significantly increased. Mechanistically, we demonstrated that surgery induced a significant increase in cytokine IL-1ß levels at day 1 after surgery, which concomitantly occurred with transcript changes in respiratory complex components. We further uncovered that transcription factors PGC-1α and NRF-1 were responsible for the observed transcript changes in mitochondrial complex components. Importantly, HT22 cells treated with the cytokine IL-1ß resulted in similar reductions in PGC-1α and NRF-1, leading to a reduction of both the transcript and protein levels of respiratory complex subunits. Consequently, respiratory function was impaired in HT22 cells treated with IL-1ß. Taken together, we demonstrated that reductions in respiratory complex components and subsequent impairment in mitochondrial functions serve as a novel mechanism for PND pathology, providing a potential therapeutic target for PND treatment.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR.

Recent studies have identified multiple RNA-binding proteins tightly associated with lipid and neuronal cholesterol metabolism and cardiovascular disorders. However, the role of heterogeneous nuclear ribonucleoprotein R (hnRNPR) in cholesterol metabolism and homeostasis, whether it has a role in regulating 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), is largely unknown. This research identifies hnRNPR as a repressor of HMGCR. Knockdown and overexpression of hnRNPR in cultured neuroblastoma cell (N2a) and MN1 cell lines enhances and inhibits HMGCR in vitro, respectively. hnRNPR may exert its repressive activity on HMGCR mRNA and protein levels by using its RNA recognition motif (RRM) in recognizing and modulating the stability of HMGCR transcript. Our RNA immunoprecipitation and luciferase reporter assays demonstrate a direct interaction between hnRNPR and HMGCR mRNA. We also demonstrated that hnRNR binds to the 3' untranslated region (3' UTR) of HMGCR and reduces its translation, while hnRNPR silencing increases HMGCR expression and cholesterol levels in MN1 and N2a cells. Overexpression of HMGCR significantly restores the decreased cholesterol levels in hnRNPR administered cells. Taken together, we identify hnRNPR as a novel post-transcriptional regulator of HMGCR expression in neuronal cholesterol homeostasis.

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000-2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9-32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

Cardiometabolic Outcomes and Mortality in Patients with Adrenal Adenomas in a Population-based Setting.

CONTEXT: While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking. OBJECTIVE: To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas. DESIGN: Population-based cohort study. SETTING: Olmsted County, Minnesota, USA. PATIENTS: Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas. MAIN OUTCOME MEASURE: Prevalence, incidence of cardiometabolic outcomes, mortality. RESULTS: (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups. CONCLUSION: Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.

hnRNPM deficiency leads to cognitive deficits via disrupting synaptic plasticity.

RNA metabolism involves complex and regulated processes, some of which include transcription, intracellular transport, translation, and degradation. The involvement of RNA binding proteins in these processes remains mostly uncharacterized regarding brain functions, especially cognition. In this study, we report that knockdown of hnRNPM in the CA1 hippocampal region of the mouse brain leads to learning and memory impairment. This finding is further supported, by the reduction of pre- and post-synaptic protein levels synaptophysin and PSD95. Notably, loss of hnRNPM affects the physiological spine in vivo by impairing the morphology of the dendritic spines. Additionally, our study demonstrates that hnRNPM directly binds to the 3'UTR of synaptophysin and PSD95 mRNAs, resulting in the stabilization of these mRNAs. Together, these findings present novel insight into the regulatory role of hnRNPM in neuronal structure and function.

Risk of bone fractures after the diagnosis of adrenal adenomas: a population-based cohort study.

OBJECTIVE: Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. DESIGN: Population-based cohort study, Olmsted County, Minnesota, USA, 1995-2017. METHODS: Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. RESULTS: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20-96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0-21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07-1.52) for developing a new fracture during follow up when compared to referent subjects. CONCLUSIONS: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Hypoparathyroidism: An Uncommon Complication Associated With Immune Checkpoint Inhibitor Therapy.

As immune checkpoint inhibitor drugs are being used in the treatment of some cancers, unusual adverse events are being reported, labeled as immune-related adverse events. Various endocrinopathies related to immune-related adverse events have been described, among which hypoparathyroidism is exceedingly rare. We report a case of hypoparathyroidism induced by immune checkpoint drugs, highlighting the need for awareness of this emerging complication.

Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study.

BACKGROUND: Adrenal tumours are commonly encountered in clinical practice, but epidemiological data mainly originate from referral centres. We aimed to determine incidence, prevalence, and rates of malignancy and hormone excess in patients with adrenal tumours in a standardised geographically well defined population. METHODS: In this retrospective population-based cohort study we assessed the standardised incidence rate of adrenal tumours in all patients with tumours who lived in Olmsted County, MN, USA, from Jan 1, 1995, to Dec 31, 2017. The Rochester Epidemiology Project infrastructure, which links medical records across all health-care providers for the entire population of Olmsted County since 1966, was used to allow researchers to identify individuals with specific diagnoses, surgical interventions, and other procedures, and to locate their medical records, which were then used in the analysis. Incidence rates and prevalence were standardised for age and sex according to the 2010 US Population. FINDINGS: An adrenal tumour was diagnosed in 1287 patients (median age 62 years; 713 (55·4%) were women; and 13 (1·0%) were children). Standardised incidence rates increased from 4·4 (95% CI 0·3-8·6) per 100 000 person-years in 1995 to 47·8 (36·9-58·7) in 2017, mainly because of the incidental discovery of adenomas less than 40 mm in diameter in patients older than 40 years. Prevalence of adrenal tumours in 2017 was 532 per 100 000 inhabitants, ranging from 13 per 100 000 in children (aged <18 years) to 1900 per 100 000 in patients older than 65 years. 111 (8·6%) of 1287 patients were diagnosed with malignancy (96 [7·5%] of whom has metastases), 14 (1·1%) with phaeochromocytoma, and 53 (4·1%) with overt steroid hormone excess. Malignancy was more common in children (62%) versus those older than 18 years (8%; p<0·0001), tumours discovered during cancer-staging or follow-up (43% vs 3% for incidentalomas; p<0·0001), tumours more than 40 mm in diameter (34% vs 6% for tumours <20 mm; p<0·0001), tumours with unenhanced CT attenuation of 30 Hounsfield units or more (20% vs 1% for <20 Hounsfield units; p<·0001), and bilateral masses (16% vs 7% for unilateral, p=0·0004). INTERPRETATION: Adrenal tumour standardised incidence rates increased 10 times from 1995 to 2017. Population-based data revealed lower rates of malignancy, phaeochromocytoma, and overt steroid hormone excess than previously reported. FUNDING: National Institutes of Health.

Cardiovascular risk and mortality in patients with active and treated hypercortisolism.

Patients with hypercortisolism demonstrate high cardiovascular morbidity and mortality, especially if diagnosis is delayed. Hypercortisolism-induced cardiovascular and metabolic comorbidities include hypertension, impaired glucose metabolism, dyslipidemia, and obesity. High prevalence of cardiovascular risk factors leads to increased rate of cardiovascular events and mortality. This risk is reduced, albeit not reversed even after successful treatment of hypercortisolism. In this review we will describe prevalence and mechanisms of cardiovascular comorbidities in patients with hypercortisolism. In addition, we will summarize the effect of therapy on cardiovascular risk factors, events, as well as mortality.

Development of a human papillomavirus type 6/11 vaccine candidate for the prevention of condyloma acuminatum.

Condyloma acuminatum (CA) represents a significant human papillomavirus (HPV) disease burden worldwide, resulting in substantial healthcare costs and loss of life quality in both genders. To address this problem, we tried to develop a bivalent HPV6/11 virus-like particle (VLP) vaccine targeting CA. HPV6/11 VLPs were generated in Hansenula polymorpha, and a disassembly and reassembly (D/R) treatment was further conducted to improve the stability and monodispersity of the VLPs. The HPV6/11 VLPs were identified by transmission electron microscopy (TEM), high performance liquid chromatography (HPLC), mass spectrum (MS) and dynamic light scattering (DLS), and were evaluated for their immunogenicity in both mice and cynomolgus monkeys. The results showed that the HPV6/11 L1 proteins were correctly expressed and assembled into HPV6/11 VLPs, and the HPV6/11 VLPs formulated with aluminum phosphate induced vigorous production of specific neutralizing antibodies against HPV6/11 VLPs in mice and cynomolgus monkeys. These data indicated that the Hansenula polymorpha-derived HPV6/11 VLPs could be formulated into a bivalent vaccine used in prevention of CA.

Activity dependent LoNA regulates translation by coordinating rRNA transcription and methylation.

The ribosome is indispensable for precisely controlling the capacity of protein synthesis. However, how translational machinery is coordinated to meet the translational demands remains elusive. Here, we identify a nucleolar-specific lncRNA (LoNA), its 5' portion binds and sequesters nucleolin to suppress rRNA transcription, and its snoRNA like 3' end recruits and diminishes fibrillarin activity to reduce rRNA methylation. Activity-dependent decrease of LoNA leads to elevated rRNA and ribosome levels, an increased proportion of polysomes, mRNA polysome loading, and protein translation. In addition, transport of ribosomes to synapses is particularly promoted, resulting in increased levels of AMPA/NMDA receptor, enhanced synaptic plasticity, long-term potentiation and consolidated memory. Strikingly, hippocampal LoNA deficiency not only enhances long-term memory in WT mice, but also restores impaired memory function in APP/PS1 transgenic mice. Together, these findings reveal the multifaceted role of LoNA in modulating ribosome biogenesis to meet the translational demands of long-term memory.

Four case reports on pelvic tumors with deep venous thromboses as main symptoms and literature review.

To probe into the reasons for misdiagnoses of pelvic tumor as deep venous thromboses as well as the diagnostic methods and effective treatments on pelvic tumor. Four case reports on misdiagnosing pelvic tumor as deep venous thromboses and further analysis on the causes of misdiagnosis, diagnosis, and treatment with the literature study. The four cases were misdiagnosed as pelvic tumor, which actually were fibroneuroma, myxo.fluidity liposarcoma, moderately differentiated squamous cell carcinoma, and synovial sarcoma, respectively. The tumor in first case was completely removed, and the tumor in other three cases, which were malignant tumors, were resected when the tumors shrank with clear boundary and less blood supply after applied with 3. cycles of intra.arterial chemotherapy via an implanted pumpies. Pelvic tumor usually show up or is misdiagnosed as deep venous thromboses for its untypical clinical manifestation, so it should be on the alert for pelvic tumor when deep venous thromboses occurs. Tumor resection is preferred for benign tumor, and intra.arterial intervention chemotherapy should be applied first for malignant tumor followed by surgery.

Clinical report of intra-arterial interventional chemotherapy for synovial sarcoma on limbs.

OBJECTIVE: The efficiency of implantable intra-arterial interventional chemotherapy before the operation for synovial sarcoma on limbs was evaluated. MATERIALS AND METHODS: Drug delivery device (chemotherapy pumps) was implanted percutaneously for 36 patients, and the interventional chemotherapy was conducted for 3-4 cycles. The surgical resection was carried out after obvious improvement was observed by clinical and imaging examination. The evaluation standard for the efficiency of chemotherapy was tumor cell necrosis rate obtained from postoperative pathological test. RESULTS: The response rate (RR) of pain alleviation was 91% (32/36), and the RR of the changing of lesion imaging was 83% (30/36). Thirty cases received extensive tumor excision, and six cases received amputation because of poor response to tumor chemotherapy and local carcinelcosis. The postoperative pathological test showed 81% moderate and severe chemotherapy response (29/36). The average follow-up time was 39 months. There were three cases presenting with local tumor recurrence, and seven deaths due to pulmonary metastasis. CONCLUSION: Intra-arterial interventional chemotherapy before operation for synovial sarcoma can effectively control pain. After chemotherapy, the imaging performance significantly changed, and tumor cells were necrotized extensively. The pathological changes were obvious.