Leveraging big data of immune checkpoint blockade response identifies novel potential targets.

BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.

A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer.

PURPOSE/OBJECTIVE(S): To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. MATERIALS/METHODS: We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54-86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3-46 months (median, 31 months). Median duration of follow-up was 36 months (range 1-54 months). We used Radiation Therapy Oncology Group and National Cancer Institute-Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. CONCLUSION: Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Low-Temperature Heat Capacity Anomalies in Ordered and Disordered Phases of Normal and Deuterated Thiophene.

We measured the specific heat Cp of normal (C4H4S) and deuterated (C4D4S) thiophene in the temperature interval of 1 ≤ T, K ≤ 25. C4H4S exhibits a metastable phase II2 and a stable phase V, both with frozen orientational disorder (OD), whereas C4D4S exhibits a metastable phase II2, which is analogous to the OD phase II2 of C4H4S and a fully ordered stable phase V. Our measurements demonstrate the existence of a large bump in the heat capacity of both stable and metastable C4D4S and C4H4S phases at temperatures of ∼10 K, which significantly departs from the expected Debye temperature behavior of Cp ≈ T3. This case study demonstrates that the identified low-temperature Cp anomaly, typically referred to as a "Boson-peak" in the context of glassy crystals, is not exclusive of disordered materials.

Immunological inflammatory biomarkers as prognostic predictors for advanced hepatocellular carcinoma.

BACKGROUND: The immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. PATIENTS AND METHODS: We enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves. RESULTS: The neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio. CONCLUSIONS: The neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy.

Double-core ionization photoelectron spectroscopy of C6H6: Breakdown of the "intuitive" ortho-meta-para binding energy ordering of K-1K-1 states.

Single-site Double-Core Hole (ss-DCH or K-2) and two-site Double-Core Hole (ts-DCH or K-1K-1) photoelectron spectra including satellite lines were experimentally recorded for the aromatic C6H6 molecule using the synchrotron radiation and multielectron coincidence technique. Density functional theory and post-Hartree-Fock simulations providing binding energies and relative intensities allow us to clearly assign the main K-2 line and its satellites. K-1K-1 states' positions and assignments are further identified using a core-equivalent model. We predict that, contrary to what has been observed in the C2H2n series of molecules, the K-1K-1 energy-level ordering in C6H6 does not reflect the core-hole distances between the two holes.

Development of Albumin Analyzer with Whole Blood and Application to Telemedicine for Patient Nutrition Management in Home Health Nursing.

Albumin level is q significant indicator of patient nutritional status. However, Point of Care Testing (POCT) devices and telemedicine system that nurses can operate easily in-home medical care is not developed. The aim of this work is the development of a POCT device for Albumin level and application to a telemedicine support system. The operability of our system was simple and easy for the nurse or patient. We believe our method is useful for Nutrition Support Team activities in-home medical care.

Detection Algorithm for Inadequate Blood Specimens Due to Contamination with an Infusion Solution in the Clinical Chemistry Tests: Prevention of Incidents by Blood Draw Error.

The aim of this work is to study the influence of contamination with infusion in clinical chemistry tests and to design an algorithm for detection of inadequate blood specimen. We show that panic value of postassium (K+)/ glucose (GLU) or decrease of total protein (TP), albumin (ALB), urea nitrogen (BUN), uric acid (UA), high-density lipoprotein cholesterol (HDL-C), total cholesterol (T-CHO), and calcium (Ca) is an index of contamination of drip infusion solution. Through a clinical study, we show that our algorithm is useful for preventing adverse medical errors.

Delayed lupus nephritis in the course of systemic lupus erythematosus is associated with a poorer treatment response: a multicentre, retrospective cohort study in Japan.

OBJECTIVE: The objective of this study was to investigate possible differences in treatment responses between two categories for the onset of lupus nephritis. METHODS: We performed a multicentre, retrospective cohort study of class III-V lupus nephritis patients diagnosed between 1997 and 2014. The renal responses to initial induction therapy were compared between patients who developed lupus nephritis within one year from diagnosis of systemic lupus erythematosus (early (E-) LN) and the remainder (delayed (D-) LN) using the Kaplan-Meier method. We determined the predictors of renal response as well as renal flares and long-term renal outcomes using multivariate Cox regression analyses. RESULTS: A total of 107 E-LN and 70 D-LN patients were followed up for a median of 10.2 years. Log-rank tests showed a lower cumulative incidence of complete response in D-LN compared with E-LN patients. Multivariate analysis identified D-LN (hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.33-0.70), nephrotic syndrome at baseline, and a chronicity index greater than 2 as negative predictors of complete response. D-LN patients were more likely to experience renal flares. D-LN (HR 2.54, 95% CI 1.10-5.83) and decreased renal function were significant predictors of chronic kidney disease at baseline. CONCLUSION: D-LN was a predictor of poorer treatment outcomes, in addition to renal histology and severity of nephritis at lupus nephritis onset.

Isoforms of Group 1 Allergens from a Tropical/Subtropical Para Grass (Urochloa mutica) Display Different Levels of IgE Reactivity and Cross-reactivity.

Summary: Group 1 grass pollen allergens, or beta-expansins, are the most important major allergens from tropical/subtropical grasses. This study aimed to investigate the sequence similarity, and immunoreactivity of group 1 allergens from Para grass (Urochloa mutica). Three isoforms (Uro m 1.01, Uro m 1.02, and Uro m 1.03) were cloned from cDNA of Para grass pollen. The acidic-neutral isoforms rUro m 1.01 and rUro m 1.02 could effectively inhibited beta-expansins in pollen extract of Bermuda and Johnson grasses, suggesting that these isoforms could be major cross-reacting allergens among these grasses. In contrast, the basic isoform rUro m 1.03 had limited IgE reactivity. Thus, group 1 allergens both acidic-neutral and basic isoforms could have markedly different IgE reactivity.

Herpetiform pemphigus with characteristic transmission electron microscopic findings of various-sized ballooning vacuoles in keratinocytes without acantholysis.

We report a unique case of a Japanese woman with herpetiform pemphigus (HP) who had IgG autoantibodies reactive with nondesmosomal sites of keratinocytes and presented characteristic transmission electron microscopic (TEM) findings of various-sized vacuoles in keratinocytes without acantholysis. The patient presented with pruritic annular oedematous erythemas with small blisters lining the margins on the trunk and extremities. Histopathological examinations showed intraepidermal blisters with prominent infiltrations of eosinophils. Direct and indirect immunofluorescence tests revealed the presence of in vivo bound and circulating IgG autoantibodies to the keratinocyte cell surfaces. However, enzyme-linked immunosorbent assays for desmoglein (Dsg) 1, Dsg3 and desmocollins 1-3 showed negative results. Immunoblotting using the full-length human Dsg1 recombinant protein showed a positive band. TEM examination showed various-sized vacuoles squashing the nuclei in many keratinocytes, resulting in rupture of the cells. Immunoelectron microscopic examination revealed IgG deposition over the entire keratinocyte cell surfaces, which spared the desmosomes. IgG antibodies were also present on the inside walls of the vacuoles around the nuclei of keratinocytes and on the cell surfaces of infiltrating eosinophils. This patient also had marked eosinophilia and high levels of thymus and activation-regulated chemokine and interleukin-5 in the serum. These results indicated a novel autoantigen on the nondesmosomal keratinocyte cell surfaces and the pathogenesis of bullous spongiotic change with inflammation in HP.

Changes in the expression of α-tocopherol-related genes in liver and mammary gland biopsy specimens of peripartum dairy cows.

Blood α-tocopherol (α-Toc) concentrations decline gradually throughout the prepartum period, reaching the nadir after calving in dairy cows. The 6 α-Toc-related molecules [α-Toc transfer protein (TTPA); afamin; scavenger receptor class B, Type I; ATP-binding cassette transporter A1; tocopherol-associated protein (SEC14L2); and cytochrome P450 family 4, subfamily F, polypeptide 2 (CYP4F2)] are expressed in liver and other peripheral tissues. These molecules could regulate α-Toc transport, blood concentrations, and metabolism of α-Toc. Therefore, the aim of this study was to evaluate the changes in the expression of α-Toc-related genes in liver and mammary gland tissues of dairy cows around calving, which have remained elusive until now. In experiment (Exp.) 1, 28 multiparous Holstein cows were used (from -5 to 6 wk relative to parturition) to monitor the changes in dietary α-Toc intake, blood concentrations of α-Toc, and lipoproteins; in Exp. 2, 7 peripartum Holstein cows were used (from -4 to 4 wk relative to parturition) for liver tissue biopsy; and in Exp. 3, 10 peripartum Holstein cows were used (from -8 to 6 wk relative to parturition) to carry out the mammary gland tissue biopsy and milk sampling. In Exp. 1, the serum α-Toc concentrations declined gradually with decreasing amount of α-Toc intake and plasma high-density lipoprotein concentrations toward calving time. However, in the early lactation period after calving, serum α-Toc concentrations remained at a lower concentration despite the recovery of α-Toc intake and plasma high-density lipoprotein concentrations. In Exp. 2, just after calving, the TTPA, SEC14L2, afamin, and albumin mRNA expression levels in the liver were temporarily downregulated, and the hepatic mRNA levels of endoplasmic reticulum stress-induced unfolded protein response markers and acute-phase response marker increased at calving. In Exp. 3, the concentrations of α-Toc in colostrum were greater than those in precolostrum (samples were collected at wk -1 relative to parturition) and mature milk. The expression of TTPA, SEC14L2, and CYP4F2 mRNA in bovine mammary gland tissue was detected. However, TTPA and SEC14L2 mRNA expressions showed the opposite trends: the expression levels of TTPA mRNA peaked whereas SEC14L2 mRNA reached a nadir at calving. These results indicate that the expression of α-Toc-related genes involved in specific α-Toc transfer and metabolism in the liver and mammary gland are altered during calving. Moreover, these changes might be associated with the maintenance of lower serum α-Toc concentrations after calving.

Relationship between bidet toilet use and haemorrhoids and urogenital infections: a 3-year follow-up web survey.

Given the growing use of electric bidet toilets in Japan and other countries, we assessed the relationship between bidet toilet use and haemorrhoids or urogenital infections. Data were collected using a web-based longitudinal survey. In total, 10 305 subjects randomly selected from panels of a Japanese website research company for the baseline survey in 2013 were asked about their frequency of bidet toilet use and receipt of a doctor's diagnosis or subjective symptom of haemorrhoids and urogenital infections. One- and three-year follow-up surveys were performed in 2014 and 2016, respectively, and information on newly diagnosed/experienced outcomes occurring during the follow-up period were collected. Cumulative incidence of haemorrhoids and urogenital infections was not significantly increased by habitual use of a bidet toilet. In men, more habitual users reported subjective symptoms of irritated skin around the anus, which were newly experienced during follow-up than non-habitual users (adjusted risk ratio 1.36 (95% confidence interval 1.06-1.75)). Further studies are needed to confirm this relationship. Several of the outcomes were significantly more prevalent in habitual users, but these results were probably explained by reverse causation.

Characterization of patients with systemic lupus erythematosus who meet the diagnostic criteria for TAFRO syndrome.

Purpose TAFRO syndrome is a novel disorder manifesting as fever, anasarca, thrombocytopenia, renal insufficiency and organomegaly, and its etiology has not been clarified. The aim of this study was to elucidate similarities and differences between systemic lupus erythematosus (SLE) and TAFRO syndrome. Methods We examined 46 consecutive patients diagnosed with SLE and determined whether they meet the proposed diagnostic criteria for TAFRO syndrome (2015 version). Results Of the 46 patients with SLE, four (8.7%) also met the TAFRO syndrome criteria (TAFRO-like group). All patients in the TAFRO-like group were males, and their mean age was significantly higher than that of the non-TAFRO group (67.5 ± 8.7 vs. 39.3 ± 18.1 years, p = 0.004). C-reactive protein and γ-glutamyl transpeptidase levels were significantly higher, and frequencies of anti-dsDNA and anti-Sm antibodies were significantly lower in the TAFRO-like than non-TAFRO group. Elder cases (onset age ≥ 50 years) met significantly more categories of the diagnostic criteria for TAFRO syndrome than did those with younger cases. Conclusions Several patients with SLE, especially elder cases, showed features similar to those of TAFRO syndrome. Although exclusion of SLE is needed in the diagnostic criteria for TAFRO syndrome, TAFRO syndrome-like SLE should be considered.

Uniaxial Magnetization Performance of Textured Fe Nanowire Arrays Electrodeposited by a Pulsed Potential Deposition Technique.

Textured ferromagnetic Fe nanowire arrays were electrodeposited using a rectangular-pulsed potential deposition technique into anodized aluminum oxide nanochannels. During the electrodeposition of Fe nanowire arrays at a cathodic potential of - 1.2 V, the growth rate of the nanowires was ca. 200 nm s-1. The aspect ratio of Fe nanowires with a diameter of 30 ± 5 nm reached ca. 2000. The long axis of Fe nanowires corresponded with the <200> direction when a large overpotential during the on-time pulse was applied, whereas it orientated to the <110> direction under the potentiostatic condition with a small overpotential. By shifting the on-time cathode potential up to - 1.8 V, the texture coefficient for the (200) plane, TC200, reached up to 1.94. Perpendicular magnetization performance was observed in Fe nanowire arrays. With increasing TC200, the squareness of Fe nanowire arrays increased up to 0.95 with the coercivity maintained at 1.4 kOe at room temperature. This research result has opened a novel possibility of Fe nanowire arrays that can be applied for a new permanent magnetic material without rare-earth metals.

High and pointed type of femoral localized reaction frequently extends to complete and incomplete atypical femoral fracture in patients with autoimmune diseases on long-term glucocorticoids and bisphosphonates.

Once a localized reaction (beaking) was detected, discontinuation of bisphosphonates (BPs) and switching to vitamin D supplementation or teriparatide therapy effectively improved its shape. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete atypical femoral fracture increased and consideration of prophylactic fixation for such patients was required. INTRODUCTION: Femoral localized reaction (localized periosteal thickening of the lateral cortex, beaking) is reported to precede atypical femoral fractures (AFFs) and to develop in 8-10% of patients with autoimmune diseases taking BPs and glucocorticoids. The aims of the present study were to retrospectively investigate the shapes of localized reaction to consider how to manage the condition. METHODS: Twenty femora of 12 patients with autoimmune diseases who were on BPs and glucocorticoids exhibited femoral localized reaction. The heights of localized reaction were measured and the shapes classified as pointed, arched, and other. Localized reaction changes were divided into three categories: deterioration, no change, and improvement. A severe form of localized reaction was defined; this was associated with prodromal pain, de novo complete AFF, or incomplete AFF with a fracture line at the localized reaction. RESULTS: The mean height of localized reaction was 2.3 ± 0.8 mm (range, 1.0-3.7 mm) and the pointed type was 35%. Localized reaction was significantly higher (3.3 ± 0.8 vs. 2.1 ± 0.7 mm; p = 0.003) and the pointed type more common (78 vs. 27%; p = 0.035) in those with the severe form of localized reaction. Seven patients with localized reactions discontinued BPs just after localized reaction was detected, but five continued on BPs for 2 years. Localized reaction deterioration was more common in patients who continued than discontinued BPs (100 vs. 29%; p = 0.027). After 2 years, all patients had discontinued BPs and localized reaction did not deteriorate further in any patient. CONCLUSIONS: Once a localized reaction was detected, discontinuation of BPs and switching to vitamin D supplementation or teriparatide therapy effectively improved it. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete AFF increased and consideration of prophylactic fixation for such patients was required.

Singlet fission in pancake-bonded systems.

We theoretically investigate the potential of pancake-bonded systems for efficient singlet fission by examining phenalenyl radical dimer and tetramer models. In the dimer model, we propose an efficient way to satisfy the excitation energy level matching required for singlet fission by tuning the diradical character by changing the intermolecular distance. In the tetramer model, electronic couplings required for both singlet fission and charge mobility are found to be maximized simultaneously in the face-to-face configuration, which is usually known to be difficult to achieve due to a trade-off relationship between them in conventional π-conjugated molecules like pentacene. In addition, on the basis of the quasi-degenerate second-order perturbation analysis, we obtain a simplified and more efficient crystal-structure design guideline that pancake-bonded systems cause highly-active singlet fission.

Electron and lattice dynamics of transition metal thin films observed by ultrafast electron diffraction and transient optical measurements.

We report the ultrafast dynamics of electrons and lattice in transition metal thin films (Au, Cu, and Mo) investigated by a combination of ultrafast electron diffraction (UED) and pump-probe optical methods. For a single-crystalline Au thin film, we observe the suppression of the diffraction intensity occuring in 10 ps, which direcly reflects the lattice thermalization via the electron-phonon interaction. By using the two-temperature model, the electron-phonon coupling constant (g) and the electron and lattice temperatures (Te, Tl) are evaluated from UED, with which we simulate the transient optical transmittance. The simulation well agrees with the experimentally obtained transmittance data, except for the slight deviations at the initial photoexcitation and the relaxed quasi-equilibrium state. We also present the results similarly obtained for polycrystalline Au, Cu, and Mo thin films and demonstrate the electron and lattice dynamics occurring in metals with different electron-phonon coupling strengths.

Postweaning changes in the expression of chemerin and its receptors in calves are associated with the modification of glucose metabolism.

Chemerin, originally known as a chemoattractant derived from adipose tissue and the liver, has been reported to have regulatory functions in gluconeogenesis, peripheral insulin sensitivity, and insulin secretion. This study was conducted to assess the postweaning changes in expression of this cytokine and its physiological role in the modification of glucose metabolism associated with weaning. Eighteen tissue samples were collected from Holstein calves (90 d of age; n = 4) to investigate the tissue distributions of chemerin and its receptors genes. was highly expressed in the liver, and secreted chemerin protein was found in the plasma. Among the receptors of chemerin, and were ubiquitously expressed whereas was predominantly expressed in the liver. The changes in glucose metabolism and expression of these genes after weaning were assessed by comparing suckling calves (n = 6) and weaned calves (n = 8) of Japanese Black cattle. No significant difference was observed in plasma glucose levels between suckling and weaned calves (P = 0.22), whereas the plasma level of total ketone bodies was significantly higher in weaned calves (P < 0.01). Plasma levels of insulin and cortisol did not differ between suckling and weaned calves. The mRNA levels of certain key enzymes involved in hepatic gluconeogenesis were also altered; for instance, level was lower in postweaning calves (P < 0.05) and () level tended to be higher after weaning (P = 0.08). However, was not altered after weaning. The plasma levels of hepatic stress indicators were also changed, with aspartate transaminase, alanine transaminase, and lactate dehydrogenase being significantly elevated in postweaning calves (P < 0.05). Chemerin protein in liver tissue was less abundant in weaned calves (P < 0.05), although there were no changes in its transcript levels. The abundance of plasma chemerin protein did not change after weaning (P = 0.95). In summary, these data indicate that as a consequence of weaning, which causes physiological stress and alters hepatic metabolism, chemerin protein expression within the liver is downregulated, indicating that chemerin plays a role in the upregulation of hepatic expression via its inhibitory effect on hepatic gluconeogenesis.

The cumulative incidence of and risk factors for latent beaking in patients with autoimmune diseases taking long-term glucocorticoids and bisphosphonates.

SUMMARY: The incidence of beaking, which has been reported to precede atypical femoral fracture, was high and increased over 2 years in patients with autoimmune diseases who were taking bisphosphonates and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking, and bisphosphonate drug holidays should be considered. INTRODUCTION: Atypical femoral fractures (AFFs) have been recently recognized as complications associated with bisphosphonate (BP) use. AFFs are considered to be stress fractures; localized periosteal thickening of the lateral cortex is often present at the fracture site; this thickening is termed "beaking." Beaking has been reported to precede AFF. The aims of the present study were to evaluate the incidence of latent beaking in patients with autoimmune diseases taking BPs and glucocorticoids and to identify risk factors for beaking. METHODS: A total of 125 patients with autoimmune diseases who were taking BPs and glucocorticoids was included; 116 patients underwent X-rays and analysis of serum and urine bone metabolic markers annually for 2 years. Mean patient age was 54.5 years; there were 105 (90.5%) females and the mean duration of disease was 13.2 years. Focal lateral cortical thickening in femoral X-rays was defined as beaking. RESULTS: Beaking was detected in 15 femora of 10 patients (8.0%) at the time of recruitment. Over the 2-year observation period, the incidence of beaking increased to 21 femora of 12 patients (10.3%), and a complete AFF at the location of beaking occurred in one patient. Beaking was associated with a longer duration of BP treatment (6.1 ± 1.0 years vs. 5.0 ± 2.9 years, p = 0.01). Age 40-60 years, BP therapy ≥4 years, and diabetes mellitus were significantly associated with beaking. CONCLUSIONS: The incidence of beaking was high, and increased over 2 years, in patients with autoimmune diseases who were taking BPs and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking. Long-term BP/glucocorticoid use was a risk factor for beaking in patients with autoimmune diseases; BP drug holidays should be considered.