Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial.

BACKGROUND: Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment. METHODS: This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete. FINDINGS: Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. INTERPRETATION: These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients. FUNDING: AbbVie.

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.

Femur 3D-DXA Assessment in Female Football Players, Swimmers, and Sedentary Controls.

Cortical and trabecular volumetric bone mineral density (vBMD), cortical thickness and surface BMD (sBMD, density-to-thickness ratio) were analyzed in the proximal femur of elite female football players and artistic swimmers using three-dimensional dual-energy X-ray absorptiometry (3D-DXA) software and compared to sedentary controls. Football players had significantly higher (p<0.05) vBMD (mg/cm3) in the trabecular (263±44) and cortical femur (886±69) than artistic swimmers (224±43 and 844±89) and sedentary controls (215±51 and 841±85). Football players had also higher (p<0.05) cortical thickness (2.12±0.19 mm) and sBMD (188±22 mg/cm2) compared to artistic swimmers (1.85±0.15 and 156±21) and sedentary controls (1.87±0.16 and 158±23). Artistic swimmers did not show significant differences in any parameter analyzed for 3D-DXA when compared to sedentary controls. The 3D-DXA modeling revealed statistical differences in cortical thickness and vBMD between female athletes engaged in weight-bearing (football) and non-weight bearing (swimming) sports and did not show differences between the non-weight bearing sport and the sedentary controls. 3D-DXA modeling could provide insight into bone remodeling in the sports field, allowing evaluation of femoral trabecular and cortical strength from standard DXA scans.

Osteoporosis and Fragility Fractures in Patients with Liver Cirrhosis: Usefulness of FRAX® as a Screening Tool.

PURPOSE: The purpose of this study is to assess the prevalence of osteoporosis and fragility fractures in patients with liver cirrhosis (LC) and determine the associated risk factors, evaluating the usefulness of FRAX® as a screening method to identify patients at a higher risk of fracture. METHODS: This was a cross-sectional study. Demographic, clinical, and analytical data were collected in a randomized sample of LC patients attending the Hepatology Department of a university hospital. We assessed the absolute risk of fracture at 10 years (FRAX®) and based on the bone mineral density (BMD), the presence of morphometric vertebral fracture with a vertebral fracture assessment (VFA), or a thoracic and lumbar X-ray and bone microarchitecture with a trabecular bone score (TBS). RESULTS: Ninety-two patients were included (71% male); the mean age was 63 ± 11.3 years. The main etiology of LC was alcoholism (52.2%), and most patients were Child-Pugh A (80.4%), with a mean model for end-stage liver disease (MELD) score of 10.1 ± 3.6. Sixteen patients (17.4%) had osteoporosis, and fifty-four (58.7%) had osteopenia. Eight patients (8.7%) had suffered at least one fragility fracture. The absolute risk of a major fracture according to FRAX without the BMD was 5.7 ± 4.5%. Risk factors associated with osteoporosis were age and the female sex. BMI > 30 was a protective factor. A FRAX cut-off point for a major fracture > 6.6% had a sensitivity of 69% and a specificity of 85% for a diagnosis of osteoporosis. CONCLUSIONS: The prevalence of osteoporosis and fractures in patients with LC is high, particularly in older women. FRAX® may be a useful method to identify candidates for bone densitometry. A FRAX value below 6.6% without the BMD can avoid unnecessary testing.

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL.

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P < .0001). High sIgM levels/signaling strongly correlated with short TTNT (P < .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = -0.68; P = .01) or iCa2+ (r = -0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P < .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.

Muscle Thickness and Echogenicity Measured by Ultrasound Could Detect Local Sarcopenia and Malnutrition in Older Patients Hospitalized for Hip Fracture.

BACKGROUND: The aim of this work was to assess whether the muscle thickness and echogenicity were associated with dysphagia, malnutrition, sarcopenia, and functional capacity in acute hospital admission for a hip fracture. METHODS: Observational study that assessed nutritional status by Global Leadership Initiative on Malnutrition, risk of dysphagia and sarcopenia by European Working Group on Sarcopenia in Older People and Barthel functional index. We measured muscle thickness and echogenicity of masseter, bicipital, and quadriceps rectus femoris (RF) and vastus intermedius (VI) by ultrasound. RESULTS: One hundred and one patients were included in the study (29.7% sarcopenia and 43.8% malnutrition). Logistic regression models adjusted for age, sex, and body mass index showed an inverse association of the masseter thickness with both sarcopenia (OR: 0.56) and malnutrition (OR: 0.38) and quadriceps with sarcopenia (OR: 0.74). In addition, patients at high risk of dysphagia had lower masseter thickness (p: 0.0001) while patients able to self-feeding had thicker biceps (p: 0.002) and individuals with mobility on level surfaces higher thickness of biceps (p: 0.008) and quadriceps (p: 0.04). CONCLUSION: Thickness of the masseter was associated with risk of dysphagia, biceps with the ability to self-feed, and that of the quadriceps RF-VI with mobility.

Predictive Value of Skeletal Muscle Mass in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Reduced muscle mass has been associated with increased treatment complications in several tumor types. We evaluated the impact of skeletal muscle index (SMI) on prognosis and immune-related adverse events (IrAEs) in a cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoints inhibitors (ICI). METHODS: A single-institutional, retrospective study was performed including 61 consecutive patients of R/M HNSCC diagnosed between July 2015 and December 2018. SMI was quantified using a CT scan at L3 to evaluate body composition. Median baseline SMI was used to dichotomize patients in low and high SMI. Kaplan-Meier estimations were used to detect overall survival (OS) and progression-free survival (PFS). Toxicity was recorded using Common Terminology Criteria for Adverse Event v4.3. RESULTS: Patients were 52 men (85.2%) with mean of age 57.7 years (SD 9.62), mainly oral cavity (n = 21; 34.4%). Low SMI was an independent factor for OS in the univariate (HR, 2.06; 95% CI, 1.14-3.73, p = 0.017) and multivariate Cox analyses (HR, 2.99; 95% CI, 1.29-6.94; p = 0.011). PFS was also reduced in patients with low SMI (PFS HR, 1.84; 95% CI, 1.08-3.12; p = 0.025). IrAEs occurred in 29 (47.5%) patients. There was no association between low SMI and IrAEs at any grade (OR, 0.56; 95% CI, 0.20-1.54; p = 0.261). However, grades 3 to 4 IrAEs were developed in seven patients of whom three had low SMI. CONCLUSIONS: Low SMI before ICI treatment in R/M HNSCC patients had a negative impact on OS and PFS. Further prospective research is needed to confirm the role of body composition as a predictive biomarker in ICI treatment.

Jumping rope and whole-body vibration program effects on bone values in Olympic artistic swimmers.

INTRODUCTION: Artistic swimming seems not to benefit bone development like other out-of-water physical activities. To increase bone acquisition, artistic swimming should combine water training with weight-bearing impact or strength activities. Artistic swimmers can be a population at risk of developing osteopenia and osteoporosis in later life. The aim of the present study was to evaluate the effects of a training program on bone mineral density (BMD), bone mineral content (BMC) and body composition in an Olympic artistic swimming team. METHODS: Sixteen women aged 17-21 years, who train 30 h/week, at the Olympic Training Centre (Barcelona, Spain), were followed up over two seasons. The 1st season involved regular artistic swimming training without specific training to reduce the risk of osteopenia. The exercise intervention, jumping rope and whole-body vibration, was added in the 2nd season. The protocol included 20 min of training 2 days per week, over a 22-week period. Dual energy x-ray absorptiometry measured the bone variables and body composition. The daily diet, medical history and bone turnover markers were evaluated. RESULTS: The intervention program increased BMD on lumbar spine (2.10%, p = 0.002), total hip (2.07%, p = 0.001), and femoral neck (2.39%, p = 0.02). Lower limb's fat mass decreased (10.17%, p = 0.038). No significant differences were found for any of the measured anthropometric characteristics between both time points in the 1st season. In conclusions, combined jump rope and vibration should be considered to reduce the risk of bone damage in artistic swimmers.

Asymmetry in the length of human humerus and radius during ontogeny.

Bilateral body structures usually present some kind of asymmetry. In humans, long bones are suitable to study asymmetries because they are subject to different stimulus that can influence their development and shape. This study focuses on asymmetries of humerus and radius length during ontogeny, with a sample of 1,421 people from Barcelona ranging in age from 0 to 22 years. Data were obtained from dual-energy X-ray absorptiometry images. The humerus results showed the existence of significant directional asymmetry to the left in neonates that progressively turns to right through ontogeny, being significant in people from 11 to 16 years. The radius results are not so evident, but it can be deduced directional asymmetry in children and adolescents, with little delay from humerus. Regarding fluctuating asymmetry, higher values have been seen in neonates and they decrease during ontogeny.

Prevalence of Sarcopenia and Whole-Body Composition in Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint deformity and disability, as well as muscle involvement. Sarcopenia is characterized by a progressive age-related loss of muscle mass and strength. AIM: The aim of this study was to evaluate the prevalence of sarcopenia and possible contributing factors associated with sarcopenia in RA patients. PATIENTS AND METHODS: Adult RA patients (n = 105) of both sexes and 100 subjects as control group (CG) matched by age, sex, and body mass index were included in this cross-sectional study. Whole-body composition was measured by dual-energy x-ray absorptiometry. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 as low muscle strength (handgrip) and low muscle mass (appendicular skeletal muscle mass [ASM] index by dual-energy x-ray absorptiometry). The association between sarcopenia and associated factors was evaluated using logistic regression analyses. RESULTS: Significantly lower percentage of lean mass and ASM were found in the whole RA group compared with controls. However, lower lean parameters (total lean mass, percentage of lean mass, and ASM) were observed only in female subjects. The ASM index was significantly lower in female subjects with RA (RA 31.0% vs CG 11.9%) without differences in male subjects. On the other hand, fat mass and most adipose indices were significantly higher in both female and male subjects with RA. Female RA patients had higher prevalence of sarcopenia and sarcopenic obesity. Through univariate logistic regression analysis, the time of corticosteroids use, cumulative corticosteroid dose, previous fragility fractures, total lean mass, and ASM were associated with sarcopenia. CONCLUSIONS: Higher prevalence of sarcopenia and sarcopenic obesity were found in female RA patients. Sarcopenia was found in younger female subjects with RA compared with healthy control subjects. Sarcopenia was associated with previous fragility fractures in female patients with RA.

Timing of Pulmonary Rehabilitation in Readmitted Patients with Severe Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Early pulmonary rehabilitation (PR), started during hospitalization or within the first month after discharge, has been shown to reduce exacerbations and improve health-related-quality of life (HRQoL) and exercise capacity. However, no randomized clinical trials (RCT) have compared the efficacy of PR started during hospitalization (DHPR) to PR initiated one month post-hospitalization (PHPR). We conducted an RCT to compare DHPR to PHPR in severe patients with COPD readmitted for exacerbations in a tertiary hospital setting. Patients were randomized to receive three months of DHPR or PHPR. Outcomes were assessed at completion of the PR programme and at months 3 and 9. A total of 53 patients (26 DHPR and 27 PHPR) were included. There were no between-group differences in the number of exacerbations (mean, 3.62 vs. 3.04 in the DHPR and PHPR groups, respectively; p = 0.403). Dyspnea in activities of daily living, exercise capacity, and all HRQoL parameters improved in the PHPR group. In the DHPR group, improvement was observed only for some HRQoL parameters. All gains in both groups were lost during follow-up. More adverse events were observed in the DHPR group (20 vs 5, p = 0.023), although none of these were clinically significant. In this sample of patients with severe COPD readmitted to the hospital for exacerbations, both approaches to PR were safe, but PHPR yielded better outcomes overall. These findings suggest that, PR should be initiated in patients with severe COPD only after hospital discharge when the patients' clinical condition has stabilized.

Microneedle systems as medical devices for esthetical treatments: A risk assessment approach.

BACKGROUND: Microneedling devices are being used as a surgical technique without a clear regulatory category. They can become dangerous considering that these kind of devices can easily be bought and used by nonqualified people. AIMS: Our aim has been to demonstrate that microneedling devices used in dermatological surgery are Medical Devices according to the current regulations. PATIENTS/METHODS: After a thorough review in the European Union and USA medical device classification, we consider microneedling systems as Class II (US) or IIa (EU). RESULTS: Therefore, they must follow the regulations established for medical devices. A risk assessment has also been made, in which the technical and scientific deficiencies in their design and manufacturing have been recognized in addition to including compulsory information for the regulatory agencies and most importantly for the final user. CONCLUSION: It can be concluded that microneedling is an interesting tool in dermatology although more information related to its safety needs to be submitted. In addition, its use by nonprofessional people does not guarantee the safety of the user.

DXA-Based 3D Analysis of the Cortical and Trabecular Bone of Hip Fracture Postmenopausal Women: A Case-Control Study.

Methods using statistical shape and appearance models have been proposed to analyze bone mineral density (BMD) in 3D from dual energy X-ray absorptiometry (DXA) scans. This paper presents a retrospective case-control study assessing the association of DXA-derived 3D measurements with osteoporotic hip fracture in postmenopausal women. Patients who experienced a hip fracture between 1 and 6 years from baseline and age-matched controls were included in this study. The 3D-SHAPER software (version 2.7, Galgo Medical, Barcelona, Spain) was used to derive 3D analysis from hip DXA scans at baseline. DXA and 3D measurements were compared between groups. Total hip areal BMD of hip fracture group as measured by DXA was 10.7% lower compared to control group. Differences in volumetric BMD (total hip) as measured by 3D-SHAPER were more pronounced in the trabecular compartment (-23.3%) than in the cortex (-8.2%). The area under the receiver operating curve was 0.742 for trabecular volumetric BMD, 0.706 for cortical volumetric BMD, and 0.712 for total hip areal BMD. Differences in the cortex were locally more pronounced at the medial aspect of the shaft, the lateral aspect of the greater trochanter, and the superolateral aspect of the neck. Marked differences in volumetric BMD were observed in the greater trochanter. This case-control study showed the association of DXA-derived 3D measurements with hip fracture. Analysis of large cohorts will be performed in future work to determine if DXA-derived 3D measurements could improve fracture risk prediction in clinical practice.

Bone mineral density and bone mineral content among female elite athletes.

INTRODUCTION: Exercise is a protective factor for the appearance of osteoporosis, but not all physical activities have the same effect on bones. Low-impact sports, like swimming, may a have a negative or no effect. The aim of the present study is to evaluate bone mineral density (BMD, g/cm2) and bone mineral content (BMC, kg) among female high performance athletes from aquatic and non-aquatic sports and to assess possible differences with sedentary controls. METHODS: Participants are elite female athletes over 18 years, from the Spanish Olympic teams, with at least 12-15 h of weekly training on aquatic sports: swimming (n = 19), synchronized swimming (n = 24) and water polo (n = 14), and elite female athletes from non-aquatic sports: professional football players of Futbol Club Barcelona team (n = 92), Spanish national volleyball (n = 26) and field hockey teams (n = 29) as well as sedentary controls (n = 126). Bone mineral density scans was performed using dual-energy X-ray absorptiometry for whole body, segmental analysis, proximal femur and lumbar spine. RESULTS: Non-aquatic female athletes have total and segments BMC and BMD values higher than those of aquatic athletes, that in turn show similar BMD values compared to controls. BMD in lumbar spine and proximal femur was higher in non-aquatic sports compared to aquatic sports athletes and both were higher than controls. CONCLUSION: BMD is not negatively compromised by the practice of aquatic sports at a highly competitive level. However, non-aquatic female athletes show a higher BMD. Time training out of the water improves BMD. Our findings suggest that swimming and synchronized swimming should be combined with weight-bearing, impact or strength activities, as they do not seem to be osteogenic sports.

Bone age as a correction factor for the analysis of trabecular bone score (TBS) in children.

Trabecular bone score (TBS) is a tool to improve evaluation of DXA scans, barely used in children. We proposed to evaluate TBS with bone age (BA) compared to chronological age (CA). In girls, TBS value using BA is constant until age 8, and in boys until age 10, and then starts to increase steadily. This data may help widen TBS use in pediatric populations. INTRODUCTION: Trabecular bone score (TBS) is a software-based tool for the analysis of DXA images to assess bone microarchitecture in the lumbar region. It is used widely in adults to improve evaluation of fracture risk, yet it has been rarely studied in children and no normal curves have been developed for pediatrics. The purpose of this study was to evaluate bone (skeletal) age compared to chronological age to determine which is better in the pediatric population since both bone age (BA) and trabecular density are equally susceptible to change in response to similar factors. METHODS: Total body, lumbar region, and non-dominant hand scans were obtained with an iDXA device in all participants. DXA scans of lumbar region for TBS analysis and AP images of non-dominant hand-for-BA were obtained for 565 children (269 female) aged 4to 19. RESULTS: Simple correlation was calculated and r2 values for TBS and chronological age were obtained by linear regression, with low correlations (0.36 for boys and 0.38 for girls), and then we created Loess curves to show the change for consecutive ages. In girls, the curve forms a U shape with a nadir point at approximately age 10. We then replaced chronological age with BA, and significant change was seen in the girls' curve, where a turning point is seen at age 8. In boys, a similar trend shows a turning point at age 10. Finally, BA-corrected TBS curves were constructed using LMS, obtaining curves with percentiles. CONCLUSIONS: The use of BA in the analysis and interpretation of TBS may help widen its use in pediatric populations by enabling the appearance of normative data, but more information is needed to confirm this finding.

Plant peroxisomes at the crossroad of NO and H2 O2 metabolism.

Plant peroxisomes are subcellular compartments involved in many biochemical pathways during the life cycle of a plant but also in the mechanism of response against adverse environmental conditions. These organelles have an active nitro-oxidative metabolism under physiological conditions but this could be exacerbated under stress situations. Furthermore, peroxisomes have the capacity to proliferate and also undergo biochemical adaptations depending on the surrounding cellular status. An important characteristic of peroxisomes is that they have a dynamic metabolism of reactive nitrogen and oxygen species (RNS and ROS) which generates two key molecules, nitric oxide (NO) and hydrogen peroxide (H2 O2 ). These molecules can exert signaling functions by means of post-translational modifications that affect the functionality of target molecules like proteins, peptides or fatty acids. This review provides an overview of the endogenous metabolism of ROS and RNS in peroxisomes with special emphasis on polyamine and uric acid metabolism as well as the possibility that these organelles could be a source of signal molecules involved in the functional interconnection with other subcellular compartments.

3D patient-specific finite element models of the proximal femur based on DXA towards the classification of fracture and non-fracture cases.

Osteoporotic bone fractures reduce quality of life and drastically increase mortality. Minimally irradiating imaging techniques such as dual-energy X-ray absorptiometry (DXA) allow assessment of bone loss through the use of bone mineral density (BMD) as descriptor. Yet, the accuracy of fracture risk predictions remains limited. Recently, DXA-based 3D modelling algorithms were proposed to analyse the geometry and BMD spatial distribution of the proximal femur. This study hypothesizes that such approaches can benefit from finite element (FE)-based biomechanical analyses to improve fracture risk prediction. One hundred and eleven subjects were included in this study and stratified in two groups: (a) 62 fracture cases, and (b) 49 non-fracture controls. Side fall was simulated using a static peak load that depended on patient mass and height. Local mechanical fields were calculated based on relationships between tissue stiffness and BMD. The area under the curve (AUC) of the receiver operating characteristic method evaluated the ability of calculated biomechanical descriptors to discriminate fracture and control cases. The results showed that the major principal stress was better discriminator (AUC > 0.80) than the volumetric BMD (AUC ≤ 0.70). High discrimination capacity was achieved when the analysis was performed by bone type, zone of fracture and gender/sex (AUC of 0.91 for women, trabecular bone and trochanter area), and outcomes suggested that the trabecular bone is critical for fracture discrimination. In conclusion, 3D FE models derived from DXA scans might significantly improve the prediction of hip fracture risk; providing a new insight for clinicians to use FE simulations in clinical practice for osteoporosis management.

Sustainable PHA production in integrated lignocellulose biorefineries.

In emerging bioeconomies, the compostable biopolymers polyhydroxyalkanoates (PHAs) are desirable products due to their similarity to petropolymers. While industrial PHA production has been growing rapidly, obtaining a cheap and sustainable carbon source is still a challenge. Among biobased feedstocks, lignocellulose is a cheap, abundant and potentially sustainable carbon source. However, because of its recalcitrance, separation and depolymerization processes that have not reached industrial maturity are usually required. Integrated biorefineries utilize a holistic approach to conversion processes to minimize feedstock price and maximize resource use. This review examines the technical feasibility of merging PHA production and lignocellulose biorefining in integrated processing facilities. Among lignocellulosic feedstocks, wood is a promising carbon source due to its mature industrial infrastructure. Among the lignocellulose components, the hemicellulose fraction is the most promising feedstock for PHA production since it is underutilized and can be combined with bioethanol production from the cellulose fraction. Fractionation processes allow separate recovery of cellulose, hemicellulose and lignin, to which PHA can be added as a co-product.

The Proteome of Fruit Peroxisomes: Sweet Pepper (Capsicum annuum L.) as a Model.

Despite of their economical and nutritional interest, the biology of fruits is still little studied in comparison with reports of other plant organs such as leaves and roots. Accordingly, research at subcellular and molecular levels is necessary not only to understand the physiology of fruits, but also to improve crop qualities. Efforts addressed to gain knowledge of the peroxisome proteome and how it interacts with the overall metabolism of fruits will provide tools to be used in breeding strategies of agricultural species with added value. In this work, special attention will be paid to peroxisomal proteins involved in the metabolism of reactive oxygen species (ROS) due to the relevant role of these compounds at fruit ripening. The proteome of peroxisomes purified from sweet pepper (Capsicum annuum L.) fruit is reported, where an iron-superoxide dismutase (Fe-SOD) was localized in these organelles, besides other antioxidant enzymes such as catalase and a Mn-SOD, as well as enzymes involved in the metabolism of carbohydrates, malate, lipids and fatty acids, amino acids, the glyoxylate cycle and in the potential organelles' movements.

A Role for RNS in the Communication of Plant Peroxisomes with Other Cell Organelles?

Plant peroxisomes are organelles with a very active participation in the cellular regulation of the metabolism of reactive oxygen species (ROS). However, during the last two decades peroxisomes have been shown to be also a relevant source of nitric oxide (NO) and other related molecules designated as reactive nitrogen species (RNS). ROS and RNS have been mainly associated to nitro-oxidative processes; however, some members of these two families of molecules such as H2O2, NO or S-nitrosoglutathione (GSNO) are also involved in the mechanism of signaling processes mainly through post-translational modifications. Peroxisomes interact metabolically with other cell compartments such as chloroplasts, mitochondria or oil bodies in different pathways including photorespiration, glyoxylate cycle or ß-oxidation, but peroxisomes are also involved in the biosynthesis of phytohormones including auxins and jasmonic acid (JA). This review will provide a comprehensive overview of peroxisomal RNS metabolism with special emphasis in the identified protein targets of RNS inside and outside these organelles. Moreover, the potential interconnectivity between peroxisomes and other plant organelles, such as mitochondria or chloroplasts, which could have a regulatory function will be explored, with special emphasis on photorespiration.