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Supplemental Figure 2. Tumor PU-H71 retention at 24 hours post-injection (quantified by standard uptake value) is not explained by plasma radiotracer exposure (quantified by plasma AUC from 10 min to 4 h post-injection, see Methods), as indicated by Spearman Test R-value.

Tumor PU-H71 retention at 24 hours post-injection (quantified by standard uptake value) is not explained by plasma radiotracer exposure (quantified by plasma AUC from 10 min to 4 h post-injection, see Methods), as indicated by Spearman Test R-value.

Supplemental Figure 1. Tumor retention of PU-H71 tracer varied considerably between patients. Tumor retention expressed as tumor:bloodpool SUV ratio (y-axis) measured on PET at 4 and 24 hours post tracer-injection.

Supplementary figures and methods

PET detects subcentimeter PU-H71 retention by breast cancer metastases. 65-year-old female with stage IV breast cancer, off-treatment. 124I-PU-H71 PET (right), CT (left), and fusion PET/CT (middle) images show corresponding axial planes of chest, obtained 24 hours post-injection. Tracer has cleared from blood (asterisk, aorta) with sustained PU-H71 retention by biopsy-proven subcentimeter pulmonary metastasis (arrow) and left internal mammary and mediastinal nodal metastases (arrowheads).

Purpose:124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging.Experimental Design:Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, Results:124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects.Conclusions:Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

PET detects PU-H71 retention by lymphoma. 62-year-old female with non-Hodgkin lymphoma. 124I-PU-H71 fusion PET/CT (left), CT (middle), and F-18 FDG fusion PET/CT (right) images show corresponding axial planes of chest. 124I-PU-H71 PET/CT obtained 24 hours post-injection. Mediastinal lymphomatous adenopathy (arrowhead) demonstrates PU-H71 avidity and FDG avidity.

Purpose: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, Results: 124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

The study objective is the correlation of thyroid function to the weight status in a study group made up of schoolchildren in Galati County. Six of ten overweight children before puberty will became obese during adulthood. PREDATORR study published in May 2014, placed our country in the top among overweight and obesity European incidence, showing a 34.7% prevalence of overweight and 31.9% obesity in subjects in the age group 20-79 years. Unfortunately the study did not offer epidemiological data regarding children population. The data obtained allow the characterization of the thyroid function in relation to weight status in school age children, in a county both in urban and rural area, taking in account that there are fewer studies in rural in this moment. It brings further information on thyroid function and pathology in pediatric obesity in relation to metabolic comorbidities. We identified an increased fT3 and TSH in obese children, sustaining the association between dyslipidemia, thyroid function, anxiety and depression, as long as the data obtained adult are still controversial.

Patients with type-2 diabetes mellitus (T2DM) have normal or increased bone mineral density (BMD) but despite that, they are characterized by an increased hip and vertebral fracture risk that involves the alteration of bone quality and not the reduction in bone mass. BMD is utilized for the diagnosis and evaluation of osteoporosis, but BMD itself cannot provide an accurate diagnosis of the individuals at increased risk of fracture and, therefore, studies have focused on identifying other risk factors that are partially or fully independent of BMD. The fracture risk score tool-FRAX® models provide information about a 10-year probability of osteoporotic fractures, but do not include risk factors specific to illness such as diabetes duration, diabetes drug therapy, glycemic control, or the presence of micro-vascular complications. Multiple markers have been investigated to provide information on the risk of fractures in patients with T2DM such as: advanced glycation end products (AGEs), insulin-like growth factor-I (IGF-I), osteocalcin (OC), adiponectin, and sclerostin, but epidemiological studies did not provide homogeneous information regarding the link between these markers and bone fragility in T2DM subjects. Markers that increase the accuracy of fracture risk estimation in patients with T2DM need to be identified and employed in current medical practice.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems., Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.

PURPOSE: (124)I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose (124)I-PU-H71 for positron emission tomography (PET) to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. EXPERIMENTAL DESIGN: Adult patients with cancer (n=30) received (124)I-PU-H71 tracer (201±12 MBq

Haematological and biochemical parameters have not yet been analysed in professional padel players. The aim of this study was to determine the basal values of these parameters and to observe the effect of a simulated competition on them, including gender-related differences. A total of 14 male professional players (age: 28.2 ± 7.9 years), and 16 female professional players (age: 29.7 ± 3.7 years) participated in this study. Players were allowed to hydrate ad libitum during the matches. Haematological and biochemical values were obtained before and after a simulated competitive padel match. The men’s group showed higher baseline values in red blood cells, haematocrit, haemoglobin, urea, creatinine, uric acid, albumin, glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), lactate dehydrogenase (LDH) and creatine kinase (CK) (p < 0.01) than the women’s group. Attending to match effect, significant differences were obtained in urea, creatinine, CK and glucose (p < 0.05). Finally, the group x match interaction revealed significant differences in serum concentrations of sodium and chloride (p < 0.05). In conclusion, high-level padel matches provoke several changes in biochemical parameters related to muscle damage and protein catabolism. Recovery and fluid intake strategies could be added regarding gender. The results obtained could be due to the differences in the intensity and volume of the simulated competition.

La facilitation neuromusculaire est utilise a la fois dans le retablissement des personnes atteintes de troublesneurologiques, traumatiques, rhumatismales et aussi chez les personnes presentant des troubles de la colonne vertebrale. Dansle cas des deviations a dominante sagittale, ces techniques sont utilisees pour retablir l'equilibre musculaire et la recuperation dela colonne vertebrale.Cette etude a pour objectif d'etablir l'efficacite des techniques de facilitation dans la correction des deviations de lacolonne vertebrale dans le plan sagittal, respectivement dans le traitement des cyphoses. Differences positives obtenues par lessujets du groupe experimental, pour lesquels ont ete utilise seulement des techniques de facilitation pour le redressement de lacyphose, ainsi que une frequence de 2 seances par semaine par rapport aux 4 sessions du groupe de controle, nous laissententendre que le role des techniques de facilitation dans la recuperation des deviations de la colonne vertebrale dans le plansagittal est majeur.Choisir et utiliser les plus adequates techniques de facilitations pour la relaxation des contractures de muscles maisaussi pour tonifier les muscles allonges au niveau de la colonne vertebrale sont dependantes du niveau des connaissances etla/les methode(s) appliquee(s) par le therapeute et le mode de communication avec le patient.

Table tennis is a complex polystructural game, where a variety of motor abilities determine success. Our research stems from the assumption that these abilities develop with age and training, and that the abilities of male athletes are in general superior to female athletes. We applied 11 motor tests of power, flexibility, coordination, speed and endurance to a sample of 76 Slovenian table tennis players (twp groups with average age 12.2 years and 14.8 years, respectively). The data were gathered during regular testing at the Faculty of Sport in Ljubljana in the years 2014 and 2017. Gender and age differences, as well as potential gender-age interactions were tested using two-way analysis of variance. The results provide a more complex picture than the initial assumption. In speed and power, which are central to table tennis, the results, as expected, improved with age and were on average better in boys than in girls. However, regarding flexibility, which is in general superior in the older group, the girls are on average superior to the boys. The overall improvement in coordination with age is smaller, with a notable interaction effect in the sense of marked improvement in boys and stagnation in girls. Basic endurance is the only ability that appears to decline from age 12 to age 15, whereby the trend is more pronounced in girls.

Granuloma annulare (GA) is a benign chronic inflammatory dermatosis, self-limited, slightly pruritic or asymptomatic in the majority of the cases, with specific clinically and histologically features, that occurs in all age groups, but it is rare in infancy. GA is associated to five clinical variants: localized, generalized, perforating, subcutaneous and arcuate dermal erythema. The etiology of GA is usually unknown, but in 60-75% of the cases it is associated with metabolic disorders (diabetes mellitus, dyslipidemia), thyroid disorders, neoplasms, infections or drug induced. We present a psoriasis case treated with anti TNFα agents, Adalimumab, that after three and a half years of treatment developed GA.

Starting from the idea that selection is essential for performance in table tennis we want to develop a set of tests by which we can investigate the general and specific motor possibilities of children, enriching in this way quantitative and qualitative the existing control samples and control rules. The recorded data in the two groups have confirmed the hypothesis, there was obvious differences in comparison of the proposed samples. Statistically, there were obtained values ​​"abnormal" and the index values ​​of "t" shows insignificant differences in the media. The set of tests proposed and applied on the experimental group has proven the validity highlighting the same motor indicators as in the control group. The recorded results from control sample that was propose in the new test highlights some functional possibilities of the sportsman who are not highlighted by applying in other types of tests.

The recovery of the motor deficit caused by neurapraxia is indispensably linked to the removal of the compression on the nerve and to a recovery strategy based on the facilitation of a motor response. The study was carried out on a 32-year-old patient with comminuted fracture of the lower third of the left femur, for which she had a surgical intervention, the fracture being stabilized using a metal plate and screws. The programme was made up of: stimulating massage, facilitation techniques in an open kinetic chain, then in a closed kinetic chain using the gym ball, the medicinal ball and the cane, exercises for the re-education of sensitivity, exercises using different objects, exercises using the wall ladder, pedalling on the ergonomic bike, etc. The results achieved confirm the hypothesis formulated in the beginning; thus, the recovery of the sensory-motor deficit was achieved in 3 months, compared to the 6-9-month period normally estimated, thus halving the recovery period.

Heat shock protein 70 (Hsp70) is a family of proteins with key roles in regulating malignancy. Cancer cells rely on Hsp70 to inhibit apoptosis, regulate senescence and autophagy, and maintain the stability of numerous onco-proteins. Despite these important biological functions in cancer, robust chemical tools that enable the analysis of the Hsp70-regulated proteome in a tumor-by-tumor manner are yet unavailable. Here we take advantage of a recently reported Hsp70 ligand to design and develop an affinity purification chemical toolset for potential use in the investigation of the endogenous Hsp70-interacting proteome in cancer. We demonstrate that these tools lock Hsp70 in complex with onco-client proteins and effectively isolate Hsp70 complexes for identification through biochemical techniques. Using these tools we provide proof-of-concept analyses that glimpse into the complex roles played by Hsp70 in maintaining a multitude of cell-specific malignancy-driving proteins.

This study investigated tennis players’ speed before, during and after the split-step, deceleration before and acceleration after the split-step in four different stroke groups in three age categories. Seven male professional, eleven male and ten female junior tennis players were recorded with video cameras at official tournaments. Using the SAGIT system, we gathered data on 8,545 split-steps. Tennis players performed a split-step in 82.9% of cases. A tennis player’s speed, deceleration and acceleration were measured 0.2 s before and after the split-step. Differences between categories and stroke groups for each of the five variables were analyzed with a two-way ANOVA. The differences between the groups of players were generally much higher in the speed before, during and after the split-step than in the deceleration before and acceleration after the split-step. Most of these differences were observed between the various stroke groups. These results suggest that players use three types of movement while performing a split-step. In the first type, which is typical of serving and returning, the speed before, during and after the split-step is lower (0.55 to 1.2 m/s). The second type of movement is characteristic of baseline strokes where tennis players achieve higher speed than in the first type (0.7 to 1.66 m/s). The third type occurs in strokes where a tennis player is moving or already at the net (0.78 to 1.9 m/s). Movement in tennis is an area that requires constant development in terms of designing and upgrading movement patterns, increasing speed and practice in specific game situations.

L’œuvre d’Henri Queffélec occupe une place à part dans la littérature de l’après-guerre. À une époque où l’humanisme paraît démodé, où le récit traditionnel est remis en question, Queffélec continue à plaider pour un unanimisme chrétien et pour une littérature ancrée dans la réalité de sa région dont il évoque si bien l’imaginaire hanté par les signes de la mort. Romancier des îles bretonnes et de la mer, observateur des mutations de son temps, il peint les catastrophes provoquées par les violences de la nature, les drames et les conflits liés aux transformations sociales. Toute cette œuvre violente et déchirée ne cesse pourtant de rêver, de nous faire rêver d'harmonie, de solidarité. Queffélec a cultivé le catholicisme social et a eu des sympathies de plus en plus marquées pour le franciscanisme. Pour lui la religion est lien entre les hommes ; elle suscite des enthousiasmes, fait vivre des communautés. Le romancier joue sur les techniques narratives, sur les points de vue, pour animer des groupes et créer une vie collective. L’écrivain accomplit alors une mission presque sacerdotale en réconciliant l’homme et le monde.