Can we "prehabilitate" pancreatic cancer patients prior to surgery? A critical appraisal of the literature.

BACKGROUND: Enhancing a patient's functional capacity to withstand the surgical stress by means of multimodal (combined exercise, nutrition and psychological interventions) prehabilitation may potentially lead to improved outcomes in pancreatic cancer surgery. METHODOLOGY: A systematic review was undertaken searching PubMed, Google Scholar and Cochrane Library databases, exploring the impact of prehabilitation in pancreatic surgery. Outcomes of interest were adherence to the prehabilitation, functional capacity, overall complications and post-operative length of stay. Pooled analysis was performed using a random-effects model. RESULTS: Twelve studies comprising of 1497 patients were included in the review. Most of the studies seem to lack a multimodal approach. Less than 50 % of the studies reported adherence, which ranged between 27 and 100 %. Functional capacity, in terms of 6-min walk test, showed improvement with prehabilitation. Among the post-operative outcomes, prehabilitation was associated with significant improvement in pulmonary complications (2.4 % versus 6.7 %, RR 0.36, CI 0.17-0.74, p = 0.01, I2 = 28%). Prehabilitation was not effective in terms of length of stay or readmission rates. CONCLUSIONS: Larger studies with multimodal prehabilitation approaches may demonstrate more consistent and clinically meaningful benefits, which would lead to a firm appreciation of its role the management of pancreatic cancer patients undergoing surgery.

IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem cells.

Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.

Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin.

PURPOSE: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults. METHODS: This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2. RESULTS: The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths. CONCLUSION: Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.

Five days of bed rest in young and old adults: Retainment of skeletal muscle mass with neuromuscular electrical stimulation.

The consequences of short-term disuse are well known, but effective countermeasures remain elusive. This study investigated the effects of neuromuscular electrical stimulation (NMES) during 5 days of bed rest on retaining lower limb muscle mass and muscle function in healthy young and old participants. One leg received NMES of the quadriceps muscle (3 × 30min/day) (NMES), and the other served as a control (CON). Isometric quadriceps strength (MVC), rate of force development (RFD), lower limb lean mass, and muscle thickness were assessed pre-and post-intervention. Muscle thickness remained unaltered with NMES in young and increased in old following bed rest, while it decreased in CON legs. In old participants, mid-thigh lean mass (MTLM) was preserved with NMES while decreased in CON legs. In the young, only a tendency to change with bed rest was detected for MTLM. MVC and early-phase RFD decreased in young and old, irrespective of NMES. In contrast, late-phase RFD was retained in young participants with NMES, while it decreased in young CON legs, and in the old, irrespective of NMES. NMES during short-term bed rest preserved muscle thickness but not maximal muscle strength. While young and old adults demonstrated similar adaptive responses in preventing the loss of skeletal muscle thickness, RFD was retained in the young only.

Effect of Immunosuppression in Risk of Developing Generalized Symptoms in Ocular Myasthenia Gravis: A Retrospective Cohort Study.

BACKGROUNDS AND OBJECTIVES: Early use of immunosuppression has been suggested to prevent generalization of ocular myasthenia gravis (OMG), but high-quality evidence is limited in this regard. We examined whether treatment with prednisone and other immunosuppressants reduce the risk of generalization in OMG. METHODS: This is a retrospective study of consecutive adults with pure OMG who had a minimum 6 months of follow-up. The main outcome was the time to developing generalized symptoms. We used propensity scores to create matched data sets of patients treated with prednisone or any immunosuppressant vs controls. We also used unmatched models with inverse probability of treatment weights (IPTW) and variable exposure times. We used Cox proportional hazards model to estimate hazard ratio (HR) for generalization, comparing treated patients vs controls. RESULTS: A total of 154 patients were included, with a mean follow-up of 87.4 ± 73 months since onset. Forty-three (28%) were generalized, and mean time to generalization from diagnosis was 24.2 ± 24.1 months. Patients who received prednisone had lower risk of generalization than controls, with pooled HR 0.43 (95% CI 0.19-1.06) for the matched model, HR 0.46 (95% CI 0.21-0.89) for the IPTW model, and for HR 0.44 (95% CI 0.23-0.81) for the time-dependent exposure model. Patients who received any immunosuppressant had lower risk of generalization, with HR 0.30 (95% CI 0.11-0.77), 0.32 (95% CI 0.14-0.70), and 0.35 (95% CI 0.15-0.80) for the matched, IPTW, and IPTW-varying exposure models, respectively. DISCUSSION: Our study provides evidence that steroidal and nonsteroidal immunosuppression in patients with OMG is associated with a reduced risk of developing generalized symptoms over time. This supports the early use of immunosuppression in this population. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that treatment of OMG with corticosteroids or nonsteroidal immunosuppressants reduces the risk of generalization.

Aortic valved homograft degeneration: surgical or transcatheter approach for repeat aortic valve replacement?

OBJECTIVES: Aortic valved allografts (homografts) have been used alternatively to mechanical or biological valve prostheses in expectation of better durability; however, homograft valves do degenerate, and redo procedures have proven challenging due to heavy wall calcification. The aim of the study was to compare the outcome of open surgical (SAVR) and transcatheter aortic valve replacement (TAVR) in degenerated homografts. METHODS: Between 1993 and 2022, 81 patients underwent repeat aortic valve procedures having previously received an aortic homograft. The redo had become necessary due to regurgitation in 85% and stenosis in 15%. Sixty-five percent underwent open surgery, 35% TAVR. RESULTS: Isolated SAVR was possible in 79%, and root procedures were necessary in 21%. TAVR was performed in 79% via transfemoral and 21% via transapical access. Median prosthetic valve size was 23 (22.3-23.2) mm in the SAVR and 26 (25.2-26.9) in the TAVR group. Thirty-day mortality was 0% in the TAVR and 7% in the SAVR group (P = n.s.). TAVR showed a significantly better outcome concerning prolonged ventilation (0 vs 21%, P = 0.013) as well as ICU (1 vs 2 days; P < 0.001) and in-hospital stay (10.5 vs 13 days; P = 0.028). Five-year survival was statistically comparable between groups, and no severe leakage was observed. CONCLUSIONS: SAVR following structural homograft degeneration shows acceptable results, but the perioperative risk remains substantial and poorly predictable. TAVR presents a reasonable and more easily accessible alternative and is associated with good short- and mid-term results. In the absence of relevant contraindications, TAVR is presently the preferred treatment option for these patients at our center.

Discordant Phenotypes of Nephritis in Patients with X-linked Agammaglobulinemia.

PURPOSE: To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles. METHODS: The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed. RESULTS: Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN. CONCLUSION: Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.

Embedding textile capacitive sensing into smart wearables as a versatile solution for human motion capturing.

This work presents a novel and versatile approach to employ textile capacitive sensing as an effective solution for capturing human body movement through fashionable and everyday-life garments. Conductive textile patches are utilized for sensing the movement, working without the need for strain or direct body contact, wherefore the patches can sense only from their deformation within the garment. This principle allows the sensing area to be decoupled from the wearer's body for improved wearing comfort and more pleasant integration. We demonstrate our technology based on multiple prototypes which have been developed by an interdisciplinary team of electrical engineers, computer scientists, digital artists, and smart fashion designers through several iterations to seamlessly incorporate the technology of capacitive sensing with corresponding design considerations into textile materials. The resulting accumulation of textile capacitive sensing wearables showcases the versatile application possibilities of our technology from single-joint angle measurements towards multi-joint body part tracking.

Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3 treatment-mediated GVL effects are Tc induced. In contrast to anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti-TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Ab in patients with AML relapse after allo-HCT.

Diffusion tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate-induced chronic kidney disease.

Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region of interest (ROI) analysis to determine changes in the cortex and medulla. In addition, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III immunohistochemistry (IHC). The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline, and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney noninvasive imaging.NEW & NOTEWORTHY Chronic kidney disease (CKD) can be characterized by inflammation and fibrosis of the kidney. Although standard of care methods have been limited in scope, safety, and spatial distribution, MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo. In this study, we performed DTI in an oxalate mouse model of CKD to systematically identify local kidney injury. DTI parameters strongly correlated with histology, blood biomarkers, hydroxyproline, and gene expression.

Mydriasis in eastern box turtles (Terrapene carolina carolina) following topical administration of proparacaine, 10% phenylephrine, and rocuronium bromide.

OBJECTIVE: To determine the mydriatic effect of topical 10% phenylephrine with 10 mg/mL rocuronium bromide and compare this protocol with and without pretreatment with proparacaine. ANIMALS STUDIED: Ten client-owned pet adult eastern box turtles (Terrapene carolina carolina). PROCEDURES: All turtles were sedated with 8 mg/kg alfaxalone intramuscularly. One group of four turtles received four 20 µL drops of 10% phenylephrine and four 20 µL drops of rocuronium bromide in the right eye. Another group of four turtles received one standard drop of proparacaine followed by four 20 µL drops of 10% phenylephrine and four 20 µL drops of rocuronium bromide in the right eye. Two control group turtles received four 20 µL drops of saline in the right eye. The left eye was untreated in all turtles. Drops of the same type were separated by 2 min while drops of different types were separated by 5 min. Pupil size was recorded at 0, 15, 30, 60, 90, 120, 180, 240, and 360 min after administration of the final drop. RESULTS: Treatment with 10% phenylephrine and rocuronium bromide resulted in pupil diameter changes from baseline that were statistically significant from zero at 60, 90, and 120 min in the non-proparacaine group and 90 min in the proparacaine group. The time to peak effect was 90 min in the proparacaine group and 75 min in the non-proparacaine group. Saline-treated pupils in the control group decreased in diameter over the study period. Overall, the treated eyes of the proparacaine group and non-proparacaine group were not different from each other, but both dilated more than the control group. CONCLUSIONS: Rocuronium bromide and 10% phenylephrine can produce effective and safe mydriasis in eastern box turtles, but there was wide interindividual variation in effectiveness. Proparacaine did not improve the mydriatic effect.

Whole-body magnetic resonance neurography in patients with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Whole-body magnetic resonance neurography (MRN) is an imaging modality that shows peripheral nerve signal change in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We aimed to explore the diagnostic potential of whole-body MRN and its potential as a monitoring tool after immunotherapy in treatment-naïve CIDP patients. METHODS: Whole-body MRN using coronal 3-dimensional short tau inversion recovery (STIR) sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) techniques was performed in patients being investigated for CIDP and in healthy controls. Baseline clinical neuropathy scales and electrophysiologic parameters were collected, and MRN findings were compared before and after CIDP treatment. RESULTS: We found highly concordant symmetrical thickening and increased T2 signal intensities in the brachial/lumbosacral plexus, femoral, or sciatic nerves in five of the eight patients with a final diagnosis of CIDP and none of the healthy controls. There were no treatment-related imaging changes in five patients with CIDP who completed a follow-up study. Diffuse, symmetrical thickening, and increased T2 signal in root, plexus, and peripheral nerves were found in two patients ultimately excluded due to a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome in addition to signal changes in the muscles, bony lesions, organomegaly, and lymphadenopathy. DISCUSSION: Whole-body MRN imaging shows promise in detecting abnormalities in proximal nerve segments in patients with CIDP. Future studies evaluating the role of MRN in assessing treatment response should consider follow-up scans after treatment durations of more than 4 months.

Exploring the contribution of nature-based solutions for environmental challenges in the Netherlands.

Nature-based solutions (NbS) offer a promising and sustainable approach to addressing multiple environmental challenges, including climate change, pollution, and biodiversity loss. Despite the potential of NbS, their actual effectiveness in solving these challenges remains uncertain. Therefore, this study evaluates the contribution of NbS implemented in a nature-inclusive scenario for six environmental challenges and associated policy targets in the Netherlands. Fifteen different NbS were applied in the scenario in urban, agricultural, aquatic, and protected nature areas, with measures like flower field margins, green roofs, groundwater level management, and river restoration. The spatially-explicit Natural Capital Model was used to quantify the effectiveness of all applied NbS at a national-scale. Results show NbS significantly contribute to simultaneously solving all six assessed environmental challenges. The most significant impact was seen in improving the quality of water bodies (+34 %), making agriculture more sustainable (+24 %), and protecting and restoring biodiversity (+22 %). The contribution of NbS to address the quality of the living environment (+13 %), climate change (+10 %), and the energy transition was less effective (+2 %). Furthermore, NbS can help to achieve sectoral policy targets at the global, EU, and national levels, including those related to the Birds Habitats Directives, carbon emission, and pesticide reduction targets. This study highlights the potential of NbS to effectively address multiple environmental challenges, although they do not provide a complete solution, and suggests that future research could focus on identifying even more effective ways to implement NbS, and to mainstream their use in policy and practice.

Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection.

Introduction: Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs). Methods and results: We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response. Conclusion: This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5) for anti-dengue-specific therapies and effective vaccination development.

Dirigent isoflavene-forming PsPTS2: 3D structure, stereochemical, and kinetic characterization comparison with pterocarpan-forming PsPTS1 homolog in pea.

Pea phytoalexins (-)-maackiain and (+)-pisatin have opposite C6a/C11a configurations, but biosynthetically how this occurs is unknown. Pea dirigent-protein (DP) PsPTS2 generates 7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene (DMDIF), and stereoselectivity toward four possible 7,2'-dihydroxy-4',5'-methylenedioxyisoflavan-4-ol (DMDI) stereoisomers was investigated. Stereoisomer configurations were determined using NMR spectroscopy, electronic circular dichroism, and molecular orbital analyses. PsPTS2 efficiently converted cis-(3R,4R)-DMDI into DMDIF 20-fold faster than the trans-(3R,4S)-isomer. The 4R-configured substrate's near ß-axial OH orientation significantly enhanced its leaving group abilities in generating A-ring mono-quinone methide (QM), whereas 4S-isomer's α-equatorial-OH was a poorer leaving group. Docking simulations indicated that the 4R-configured ß-axial OH was closest to Asp51, whereas 4S-isomer's α-equatorial OH was further away. Neither cis-(3S,4S)- nor trans-(3S,4R)-DMDIs were substrates, even with the former having C3/C4 stereochemistry as in (+)-pisatin. PsPTS2 used cis-(3R,4R)-7,2'-dihydroxy-4'-methoxyisoflavan-4-ol [cis-(3R,4R)-DMI] and C3/C4 stereoisomers to give 2',7-dihydroxy-4'-methoxyisoflav-3-ene (DMIF). DP homologs may exist in licorice (Glycyrrhiza pallidiflora) and tree legume Bolusanthus speciosus, as DMIF occurs in both species. PsPTS1 utilized cis-(3R,4R)-DMDI to give (-)-maackiain 2200-fold more efficiently than with cis-(3R,4R)-DMI to give (-)-medicarpin. PsPTS1 also slowly converted trans-(3S,4R)-DMDI into (+)-maackiain, reflecting the better 4R configured OH leaving group. PsPTS2 and PsPTS1 provisionally provide the means to enable differing C6a and C11a configurations in (+)-pisatin and (-)-maackiain, via identical DP-engendered mono-QM bound intermediate generation, which PsPTS2 either re-aromatizes to give DMDIF or PsPTS1 intramolecularly cyclizes to afford (-)-maackiain. Substrate docking simulations using PsPTS2 and PsPTS1 indicate cis-(3R,4R)-DMDI binds in the anti-configuration in PsPTS2 to afford DMDIF, and the syn-configuration in PsPTS1 to give maackiain.

Isoform-selective TGF-ß3 inhibition for systemic sclerosis.

BACKGROUND: Transforming growth factor ß (TGF-ß) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in a range of homeostatic functions presents challenges to its safe and effective therapeutic targeting. There are three isoforms of TGF-ß, TGF-ß1, TGF-ß2, and TGF-ß3, which bind to a common receptor complex composed of TGF-ßR1 and TGF-ßR2 to induce similar intracellular signals in vitro. We have recently shown that the cellular expression patterns and activation thresholds of TGF-ß2 and TGF-ß3 are distinct from those of TGF-ß1 and that selective short-term TGF-ß2 and TGF-ß3 inhibition can attenuate fibrosis in vivo without promoting excessive inflammation. Isoform-selective inhibition of TGF-ß may therefore provide a therapeutic opportunity for patients with chronic fibrotic disorders. METHODS: Transcriptomic profiling of skin biopsies from patients with systemic sclerosis (SSc) from multiple clinical trials was performed to evaluate the role of TGF-ß3 in this disease. Antibody humanization, biochemical characterization, crystallization, and pre-clinical experiments were performed to further characterize an anti-TGF-ß3 antibody. FINDINGS: In the skin of patients with SSc, TGF-ß3 expression is uniquely correlated with biomarkers of TGF-ß signaling and disease severity. Crystallographic studies establish a structural basis for selective TGF-ß3 inhibition with a potent and selective monoclonal antibody that attenuates fibrosis effectively in vivo at clinically translatable exposures. Toxicology studies suggest that, as opposed to pan-TGF-ß inhibitors, this anti-TGF-ß3 antibody has a favorable safety profile for chronic administration. CONCLUSION: We establish a rationale for targeting TGF-ß3 in SSc with a favorable therapeutic index. FUNDING: This study was funded by Genentech, Inc.

Relationship between dietary characteristics and heel quantitative ultrasound parameters in postmenopausal women from the OsteoLaus cohort.

The role of dietary patterns in the development of osteoporosis is unclear. The heel quantitative ultrasound (QUS) is a potential alternative to Dual X-Ray Absorptiometry. Nutrients, foods, dietary patterns and compliance to dietary guidelines were compared between the lowest and the highest tertiles of QUS parameters [Broadband Ultrasound Attenuation (BUA), Speed of Sound (SOS), Stiffness Index (SI)], using data from the OsteoLaus cohort. Participants in the highest tertiles of QUS parameters (385 for BUA, 397 for SOS, 386 for SI) were younger, of higher body weight, and had less major osteoporotic fractures. Women in the highest tertiles of SI and BUA consumed more fat (35.1 ± 0.4 vs 33.9 ± 0.4 and 34.9 ± 0.4 vs 33.8 ± 0.4 gr/day for SI and BUA, respectively, p < 0.05), and complied less frequently with dairy intake guidelines [odds ratio (95% confidence interval): 0.70 (0.53-0.92) and 0.72 (0.55-0.95) for SI and BUA, respectively, p < 0.05] than women in the lowest tertile. No differences were found regarding dietary patterns, healthy dietary scores, or compliance to dietary guidelines. Postmenopausal women in the highest QUS tertiles were younger, of higher weight and BMI, consumed more monounsaturated fatty acids and less dairy and calcium than women in the lowest tertiles. No differences were found between QUS tertiles regarding dietary patterns.