Phase I/II clinical trial of adoptive cell transfer of sorted specific T cells for metastatic melanoma patients.

Adoptive cell transfer (ACT) of tumor-specific T lymphocytes represents a relevant therapeutic strategy to treat metastatic melanoma patients. Ideal T-cells should combine tumor specificity and reactivity with survival in vivo, while avoiding autoimmune side effects. Here we report results from a Phase I/II clinical trial (NCT02424916, performed between 2015 and 2018) in which 6 metastatic HLA-A2 melanoma patients received autologous antigen-specific T-cells produced from PBMC, after peptide stimulation in vitro, followed by sorting with HLA-peptide multimers and amplification. Each patient received a combination of Melan-A and MELOE-1 polyclonal specific T-cells, whose specificity and anti-tumor reactivity were checked prior to injection, with subcutaneous IL-2. Transferred T-cells were also characterized in terms of functional avidity, diversity and phenotype and their blood persistence was evaluated. An increase in specific T-cells was detected in the blood of all patients at day 1 and progressively disappeared from day 7 onwards. No serious adverse events occurred after this ACT. Clinically, five patients progressed and one patient experienced a partial response following therapy. Melan-A and MELOE-1 specific T-cells infused to this patient were diverse, of high avidity, with a high proportion of T lymphocytes co-expressing PD-1 and TIGIT but few other exhaustion markers. In conclusion, we demonstrated the feasibility and safety of ACT with multimer-sorted Melan-A and MELOE-1 specific T cells to metastatic melanoma patients. The clinical efficacy of such therapeutic strategy could be further enhanced by the selection of highly reactive T-cells, based on PD-1 and TIGIT co-expression, and a combination with ICI, such as anti-PD-1.

Soluble HLA-I/peptide monomers mediate antigen-specific CD8 T cell activation through passive peptide exchange with cell-bound HLA-I molecules.

Accumulating evidence that serum levels of soluble class I HLA molecules (sHLA-I) can, under various pathological conditions, correlate with disease stage and/or patient survival, has stimulated interest in defining whether sHLA-I can exert immunological functions. However, despite a mounting number of publications suggesting the ability of sHLA-I to affect immune effectors in vitro, the precise underlying mechanism still remains controversial. In this article, we address potential functions of both classical and nonclassical sHLA-I, using soluble recombinant HLA-I/peptide monomers, and clearly demonstrate their ability to trigger Ag-specific activation of CD8 T cells in vitro. Furthermore, we provide strong evidence that this behavior results from the passive transfer of peptides from monomers to T cell-bound HLA-I molecules, allowing for fratricide representation and activation. Hence, we proposed a unifying model of T cell activation by HLA-I/peptide monomers, reappraising the potential involvement of sHLA-I molecules in the immune response.

CD137 on inflamed lymphatic endothelial cells enhances CCL21-guided migration of dendritic cells.

CD137/TNFR9/41BB was originally described as a surface molecule present on activated T and NK cells. However, its expression is broader among leukocytes, and it is also detected on hypoxic endothelial cells and inflamed blood vessels, as well as in atherosclerotic lesions. Here, we demonstrate that lymphatic endothelial cells (LECs) up-regulate CD137 expression from undetectable baseline levels on stimulation with TNF-α, LPS, and IL-1ß. CD137 cross-linking with an agonistic mAb results in NF-κB nuclear translocation, followed by up-regulation of VCAM and a 3-fold increase in the production of the chemokine CCL21. Accordingly, there is a 50% increase in CCR7-dependent migration toward conditioned medium from activated LECs on CD137 cross-linking with the agonistic mAb or the natural ligand (CD137L). Such an enhancement of cell migration is also observed with monocyte-derived dendritic cells transmigrating across CD137-activated LEC monolayers. Using explanted human dermal tissue, we found that inflamed skin contains abundant CD137(+) lymphatic vessels and that ex vivo incubation of explanted human dermis with TNF-α induces CD137 expression in lymphatic capillaries. More interestingly, treatment with CD137 agonistic antibody induces CCL21 expression and DC accumulation close to lymphatic vessels. Collectively, our results demonstrate that the inflammatory function of lymphatic vessels can be regulated by CD137.

Mechanisms and predictors of menses resumption once normal weight is reached in anorexia nervosa.

BACKGROUND: In cases of Anorexia Nervosa (AN), achieving weight gain recovery beyond the lower limits set by the World Health Organization and normalizing classical nutritional markers appears to be essential for most patients. However, this is not always adequate to restore menstrual cycles. This discrepancy can cause concern for both patients and healthcare providers, and can impact the medical management of these individuals. Thus, the purpose of this study was to assess the ability of anthropometric and hormonal factors to predict the resumption of menstrual cycles in individuals with anorexia nervosa upon reaching a normal body weight. METHOD: Patients with AN who had achieved a normal Body Mass Index but had not yet resumed their menstrual cycles (referred to as ANRec) were evaluated on two occasions: first at visit 1 and then again 6 months later, provided their body weight remained stable over this period (visit 2). Among the 46 ANRec patients who reached visit 2, they were categorized into two groups: 20 with persistent amenorrhea (PA-ANRec) and 26 who had regained their menstrual cycles (RM-ANRec). Anthropometric measurements, several hormone levels, Luteinizing Hormone (LH) pulsatility over a 4-h period, and LH response to gonadotropin-releasing hormone injection (LH/GnRH) were then compared between the two groups at visit 1. RESULTS: Patients in the RM-ANRec group exhibited higher levels of follicular stimulating hormone, estradiol, inhibin B, LH/GnRH, and lower levels of ghrelin compared to those in the PA-ANRec group. Analysis of Receiver Operating Characteristic curves indicated that having ≥ 2 LH pulses over a 4-h period, LH/GnRH levels ≥ 33 IU/l, and inhibin B levels > 63 pg/ml predicted the resumption of menstrual cycles with a high degree of specificity (87%, 100%, and 100%, respectively) and sensitivity (82%, 80%, and 79%, respectively). CONCLUSIONS: These three hormonal tests, of which two are straightforward to perform, demonstrated a high predictive accuracy for the resumption of menstrual cycles. They could offer valuable support for the management of individuals with AN upon achieving normalized weight. Negative results from these tests could assist clinicians and patients in maintaining their efforts to attain individualized metabolic targets. TRIAL REGISTRATION: IORG0004981.

Once a minimally normal weight has been reached during eating disorder recovery for female patients with anorexia nervosa (AN), the persistence of amenorrhea can be a cause for concern both patient and practitioner. In our study, we have discovered that positive results in biological blood tests, which can be conveniently conducted in an ambulatory setting, offer valuable predictive insights. Specifically, parameters such as LH pulse numbers exceeding 2, LH response to GnRH injection surpassing 33 UI/L, or Inhibin B levels in the blood exceeding 63 pg/mL, can accurately predict the resumption of menstrual cycles in the upcoming months, provided that the patient does not experience weight loss or engage in intense exercise. Conversely, negative results from these tests at this critical juncture in the recovery process can serve as valuable tools to encourage and motivate both the healthcare provider and the patient. By maintaining their efforts and continuing to increase their weight, patients can work towards a more comprehensive restoration of their menstrual cycles.

Normal inhibin B levels suggest partial preservation of gonadal function in adult male patients with anorexia nervosa.

INTRODUCTION: The impact of undernutrition on endocrine and exocrine gonadatrope function is poorly known in male anorexia nervosa (AN) patients. AIM: The aim of this study was to compare the pituitary-gonadal function of male AN subjects with that of healthy controls, Kallmann syndrome (KS) patients, and female AN subjects. METHODS: Observational monocentric cross-sectional study performed in 31 male and 25 female subjects with restrictive-type AN, 22 male and 20 female controls, and nine male KS patients. MAIN OUTCOME MEASURES: Hormonal parameters are as follows: follicule stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, estradiol, testosterone, inhibin B, thyroid hormones, growth hormone (GH), insulin-like growth factor 1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and leptin. RESULTS: Similar abnormalities of free T3, GH, IGF-I, cortisol, and leptin were found in men as in AN women with equivalent undernutrition status when compared with corresponding controls. Low levels of LH, FSH were found in both male and female AN patients. In male AN, total testosterone was found lower than in controls but higher than in KS, while a lack of estradiol was noticed in AN women. Sex hormones variations were directly related to weight gain only in AN men. No relationship was found between sex hormones and leptin variation for both sexes. In AN men, inhibin B levels were similar to that of controls and did not correlate with testosterone levels. CONCLUSIONS: Significant differences of undernutrition impact on gonadal status were noticed between male and female AN subjects, including partial preservation of testosterone release and probable preservation of exocrine function, according to the normal inhibin B levels.

The angiogenic growth factor and biomarker midkine is a tumor-shared antigen.

The angiogenic factor Midkine (MDK) is overexpressed in various human malignant tumors, although its expression is low or undetectable in normal adult tissues. Its expression in tumors and its detection in plasma have been associated with poor disease outcome, whereas its blockade was found to contribute to tumor regression. By weekly stimulation of T lymphocytes harvested in HLA-A2 healthy donors, we derived CD8 T cell lines specific for several MDK peptides. The T cell response was mostly dominated by two nonamer peptides localized in the signal peptide and in the C-terminal part of the protein, as assessed by IFN-gamma ELISPOT and HLA-A2 tetramer labeling. Peptide-specific T cell lines recognized cells transfected with an MDK-encoded plasmid and tumor cell lines naturally expressing the MDK protein, but not untransfected cells. T cell presentation of the two MDK epitopes was found to be TAP dependent. Experiments performed in HLA-A2 transgenic mice demonstrated the capacity of the two identified CD8 T cell epitopes to elicit a cytotoxic response. Altogether, our data show that the secreted MDK protein is a candidate vaccine for multiple cancers.

Is there any impact of cognitive remediation on an ecological test in schizophrenia?

INTRODUCTION: Cognitive deficits are commonly reported in schizophrenia and have a significant impact on the daily life of patients and on their social and work inclusion. Cognitive remediation therapies (CRT) may enhance the capabilities of schizophrenia patients. Although social and work integration is the ultimate goal of CRT, previous studies have failed to carry out a detailed assessment of the effects on everyday life. METHODS: Fifty-nine schizophrenia patients were randomised into two groups (remediation or usual treatment) to test the effects of a new remediation programme, which included both rehearsal and strategy learning, on cognitive functions. An ecological test was used to evaluate its transfer to daily living skills. RESULTS: Cognitive improvements are revealed in CRT patients, mainly in memory and executive functions. Patients showing some deficiencies to perform the ecological test had better scores after the CRT. Moreover, they significantly improve their social activity scores. CONCLUSIONS: CRT would facilitate mental load monitoring by enhancing or reallocating cognitive resources, facilitating the patient's organisation and autonomy. The rehearsal learning approach improves the ability to carry out automatic operations that are less demanding in terms of cognitive resources, thereby increasing the resources available for acquisition and efficient use of strategies provided during the strategy learning approach.

hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote MELOE-1 translation in stressed melanoma cells.

The major challenge in antigen-specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma-specific antigen, melanoma-overexpressed antigen 1 (MELOE-1)-coded for by a long noncoding RNA-whose internal ribosomal entry sequence (IRES)-dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad-specific T-cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE-1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) binds to the MELOE-1 IRES and acts as an IRES trans-activating factor (ITAF) to promote the translation of MELOE-1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP-A1 cytoplasmic translocation, enhances MELOE-1 translation and recognition of melanoma cells by a MELOE-1-specific T-cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress-induced tumor antigens such as MELOE-1.

A long peptide from MELOE-1 contains multiple HLA class II T cell epitopes in addition to the HLA-A*0201 epitope: an attractive candidate for melanoma vaccination.

CD4(+) T cells contribute importantly to the antitumor T cell response, and thus, long peptides comprising CD4 and CD8 epitopes may be efficient cancer vaccines. We have previously identified an overexpressed antigen in melanoma, MELOE-1, presenting a CD8(+) T cell epitope, MELOE-1(36-44), in the HLA-A*0201 context. A T cell repertoire against this epitope is present in HLA-A*0201+ healthy subjects and melanoma patients and the adjuvant injection of TIL containing MELOE-1 specific CD8(+) T cells to melanoma patients was shown to be beneficial. In this study, we looked for CD4(+) T cell epitopes in the vicinity of the HLA-A*0201 epitope. Stimulation of PBMC from healthy subjects with MELOE-1(26-46) revealed CD4 responses in multiple HLA contexts and by cloning responsive CD4(+) T cells, we identified one HLA-DRß1*1101-restricted and one HLA-DQß1*0603-restricted epitope. We showed that the two epitopes could be efficiently presented to CD4(+) T cells by MELOE-1-loaded dendritic cells but not by MELOE-1+ melanoma cell-lines. Finally, we showed that the long peptide MELOE-1(22-46), containing the two optimal class II epitopes and the HLA-A*0201 epitope, was efficiently processed by DC to stimulate CD4(+) and CD8(+) T cell responses in vitro, making it a potential candidate for melanoma vaccination.

An additional ORF on meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-specific T cells in the HLA-A2 context.

We characterized a new melanoma antigen derived from one of the multiple open reading frames (ORFs) of the meloe transcript. The meloe gene is overexpressed in melanomas as compared to other cancer cell lines and normal tissues. The corresponding transcript is rather unusual, in that it does not contain a long unique ORF but multiple short ORFs. We recently characterized a tumor epitope derived from a polypeptide (MELOE-1) encoded by the ORF(1230-1370) and involved in relapse prevention of melanoma patients treated with autologous tumor infiltrating lymphocytes (TIL). Here we show that the ORF(285-404) encodes a polypeptide called MELOE-2 that also generated a HLA-A2 epitope recognized by a melanoma-specific T cell clone derived from the same TIL population from which we derived the MELOE-1-specific T cell clone. We also showed that HLA-A2 melanoma cells were spontaneously recognized by the MELOE-2-specific T cell clone, and we detected the presence of MELOE-2 reactive T cells in another TIL population infused to a patient who remained relapse-free after TIL treatment. These results demonstrate that translation of meloe transcript in melanoma cells can produce at least two immunogenic polypeptides, MELOE-1 and MELOE-2, from two distinct ORFs that could be relevant target for melanoma immunotherapy.

Synthesis of N-aryl-3-(indol-3-yl)propanamides and their immunosuppressive activities.

N-aryl-3-(indol-3-yl)propanamides were synthesized and their immunosuppressive activities were evaluated. This study highlighted the promising potency of 3-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(4-nitrophenyl)propanamide 15 which exhibited a significant inhibitory activity on murine splenocytes proliferation assay in vitro and on mice delayed-type hypersensitivity (DTH) assay in vivo.

CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice.

BACKGROUND: Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis. METHODS AND RESULTS: This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E-deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8(+) cells, and expression of the murine major histocompatibility complex class II molecule I-A(b) increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines. CONCLUSIONS: Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

A fast and efficient HLA multimer-based sorting procedure that induces little apoptosis to isolate clinical grade human tumor specific T lymphocytes.

HLA multimers are now widely used to stain and sort CD8 T lymphocytes specific for epitopes from viral or tumoral antigens presented in an HLA class I context. However, the transfer of this technology to a clinical setting to obtain clinical grade CD8 T lymphocytes that may be used in adoptive cell transfer (ACT) is hindered by two main obstacles: the first obstacle is the use of streptavidin or derived products that are not available in clinical grade to multimerize HLA/peptide monomers and the second is the reported high degree of apoptosis that eventually occurs when T cell receptors are crosslinked by HLA multimers. In the present report, we describe new HLA multimers composed of immunomagnetic beads covalently coupled to a mAb specific for the AviTag peptide and coated with HLA/peptide monomers bearing the non biotinylated AviTag at the COOH terminus of the HLA heavy chain. Thus, all the components of this new reagent can be obtained in clinical grade. We compared these new multimers with the previously described multimers made with streptavidin beads coated with biotinylated HLA/peptide monomers, in terms of sorting efficiency, recovery of functional T cells, apoptosis and activation. We provide evidence that the new multimers could very efficiently sort pure populations of T lymphocytes specific for three different melanoma antigens (Melan-A, gp100 and NA17-A) after a single peptide stimulation of melanoma patients' PBMC. The recovered specific T cells were cytotoxic against the relevant melanoma cell-lines and, in most cases, produced cytokines. In addition, in marked contrast with streptavidin-based multimers, our new multimers induced very little apoptosis or activation after binding specific T lymphocytes. Altogether, these new multimers fulfill all the necessary requirements to select clinical grade T lymphocytes and should facilitate the development of ACT protocols in cancer patients.

A novel indole-3-propanamide exerts its immunosuppressive activity by inhibiting JAK3 in T cells.

We previously identified an indole-3-propanamide derivative, 3-[1-(4-chlorobenzyl)indol-3-yl]-N-(pyridin-4-yl)propanamide (AD412), as a potential immunosuppressive agent. Here, we document that AD412 inhibited the proliferative response of CD3/CD28-stimulated human T cells without inhibiting their interleukin 2 (IL-2) production and also inhibited the proliferation of CTL-L2 cells in response to IL-2. These results prompted us to analyze the effect of our compound on the three main signaling pathways coupled to the IL-2 receptor. We provide evidence that AD412 inhibited the JAK1/3-dependent phosphorylations of Akt, STAT5a/b, and ERK1/2 in IL-2-stimulated CTL-L2 cells. In contrast, AD412 had little effect on the JAK1/2-dependent INF-gamma-induced phosphorylation of STAT1 in U266 cells. This suggested a preferential inhibition of JAK3 over JAK1 or JAK 2 activities by AD412 that was confirmed by in vitro kinase assays with purified JAK2 and JAK3 kinases. In addition, we provide evidence that the inhibition of IL-2 response by AD412 was not due to inhibition of IL-2Ralpha up-regulation because neither AD412 nor JAK3 inhibitors described previously [4-[(3-bromo-4-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (WHI-P154) and alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamid (AG-490)] significantly inhibited IL-2-induced IL-2Ralpha overexpression. Finally, we further document the immunosuppressive activity of AD412 in vivo by showing that its administration per os significantly prolonged heart allograft graft survival. This molecule may thus represent an interesting lead compound to develop new immunosuppressive agents in the field of transplantation and autoimmune diseases.

Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosa.

Constitutional thinness (CT) and anorexia nervosa (AN) are two categories of severely underweight subjects. Some appetite-regulating hormones display opposite levels in AN and CT. While levels of ghrelin, an orexigenic hormone, fit with the normal food intake in CT, the lack of efficacy of increased ghrelin levels in AN is not clear. Obestatin is a recently described peptide derived from the preproghrelin gene, reported to inhibit appetite in contrast to ghrelin. The aim of this study was to determine whether the circadian profile of obestatin, total and acylated ghrelin levels is different in CT subjects when compared with AN patients. Six-points circadian profiles of plasma obestatin, acylated ghrelin, total ghrelin and other hormonal and nutritional parameters were evaluated in four groups of young women: 10 CT, 15 restricting-type AN, 7 restored from AN and 9 control subjects. Obestatin circadian levels were significantly higher in AN (p<0.0001) while no difference was found between CT and control subjects. Acylated and total ghrelin were found increased in AN. Acylated ghrelin/obestatin and total ghrelin/obestatin were found decreased in AN compared to CT or C subjects (p<0.05). The percentage of acylated ghrelin was found decreased in CT group (p<0.05). The decreased ghrelin/obestatin ratio found in AN might participate in the restraint in nutriment intake of these patients. In contrast, in CT a lower percentage of acylated over total ghrelin might be considered in the aetiology of this condition.

Brain activation during executive processes in schizophrenia.

Schizophrenia patients show some deficits in executive processes (impaired behavioural performance and abnormal brain functioning). The aim of this study is to explore the brain activity of schizophrenia patients during different inhibitory tasks. We used functional magnetic resonance imaging to investigate to investigate the restraint and deletion aspects of inhibition in 19 patients with schizophrenia and 12 normal subjects during the performance of the Hayling and the N-back tasks. The patients demonstrated impaired performance (more errors and longer reaction times) in the Hayling task. Schizophrenia subjects activated the same fronto-parietal network as the control subjects but demonstrated stronger parietal activations. For the N-back task, the deficit shown by the patients was limited to the number of target omissions. The reaction times and the number of false alarms did not differ in the two groups. We interpret this pattern of deficit as an alteration of working memory processes (and unaltered inhibition). Schizophrenia subjects showed higher activations in a fronto-parietal network. Since schizophrenia patients reached normal inhibitory performances in the N-back task and not in the Hayling task, the frontal hyperactivation may reflect an increased effort or a compensatory mechanism that facilitates the performance of executive tasks. During the Hayling task, this frontal hyperactivation was not achieved, and its absence was associated with a performance deficit relative to the performance of normal subjects.

Cancer vaccines: designing artificial synthetic long peptides to improve presentation of class I and class II T cell epitopes by dendritic cells.

There is now a consensus that efficient peptide vaccination against cancer requires that peptides should (i) be exclusively presented by professional APC and (ii) stimulate both CD4 and CD8-specific T cell responses. To this aim, in recent trials, patients were vaccinated with pools of synthetic long peptides (SLP) (15-30 aa long) composed of a potential class I epitope(s) elongated at both ends with native antigen sequences to also provide a potential class II epitope(s). Using MELOE-1 as a model antigen, we present an alternative strategy consisting in linking selected class I and class II epitopes with an artificial cathepsin-sensitive linker to improve epitope processing and presentation by DC. We provide evidence that some linker sequences used in our artificial SLPs (aSLPs) could increase up to 100-fold the cross-presentation of class I epitopes to CD8-specific T cell clones when compared to cross-presentation of the corresponding native long peptide. Presentation of class II epitopes were only slightly increased. We confirmed this increased cross-presentation after in vitro stimulation of PBMC from healthy donors with aSLP and assessment of CD8-specific responses and also in vivo following aSLP vaccination of HLA*A0201/HLA-DRB0101 transgenic mice. Finally, we provide some evidence that vaccination with aSLP could inhibit the growth of transplanted tumors in mice. Our data thus support the use of such aSLPs in future cancer vaccination trials to improve anti-tumor CD8 T cell responses and therapeutic efficacy.

Constitutional thinness: unusual human phenotype of low bone quality.

CONTEXT: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile. OBJECTIVE: Our objective was to determine whether constitutional thinness is associated with impaired bone quality. DESIGN, SETTING, AND PARTICIPANTS: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls. MAIN OUTCOME MEASURES: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined. RESULTS: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor kappa B ligand ratio was higher in constitutionally thin subjects than in controls or AN women. CONCLUSIONS: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.

Risk factors for addictive disorders: a discriminant analysis on 374 addicted and 513 nonpsychiatric participants.

Many common risk factors have been described in addictive disorders. Little is known about factors' respective contributions to discrimination of addicted and nonaddicted participants. Two large samples were compared including 513 nonpsychiatric participants and 374 addicted participants meeting the DSM-IV criteria for eating disorders, alcohol, or substance dependence. Twenty-six risk factors were assessed by interview or self-rating scales. A discriminant analysis determined the respective weight of each risk factor. One discriminant function emerged and characterized a depressive dimension. The results suggest that the different risk factors described in addiction could be related to a depressive dimension.

A dataset of 200 structured product labels annotated for adverse drug reactions.

Adverse drug reactions (ADRs), unintended and sometimes dangerous effects that a drug may have, are one of the leading causes of morbidity and mortality during medical care. To date, there is no structured machine-readable authoritative source of known ADRs. The United States Food and Drug Administration (FDA) partnered with the National Library of Medicine to create a pilot dataset containing standardised information about known adverse reactions for 200 FDA-approved drugs. The Structured Product Labels (SPLs), the documents FDA uses to exchange information about drugs and other products, were manually annotated for adverse reactions at the mention level to facilitate development and evaluation of text mining tools for extraction of ADRs from all SPLs. The ADRs were then normalised to the Unified Medical Language System (UMLS) and to the Medical Dictionary for Regulatory Activities (MedDRA). We present the curation process and the structure of the publicly available database SPL-ADR-200db containing 5,098 distinct ADRs. The database is available at https://bionlp.nlm.nih.gov/tac2017adversereactions/; the code for preparing and validating the data is available at https://github.com/lhncbc/fda-ars.