Cellular Griffiths-like phase.

Protein compartmentalization in the frame of a liquid-liquid phase separation is a key mechanism to optimize spatiotemporal control of biological systems. Such a compartmentalization process reduces the intrinsic noise in protein concentration due to stochasticity in gene expression. Employing Flory-Huggins solution theory, Avramov/Casalini's model, and the Grüneisen parameter, we unprecedentedly propose a cellular Griffiths-like phase (CGLP), which can impact its functionality and self-organization. The here-proposed CGLP is key ranging from the understanding of primary organisms' evolution to the treatment of diseases. Our findings pave the way for an alternative Biophysics approach to investigate coacervation processes.

Immune cell infiltration and inflammatory landscape in primary brain tumours.

BACKGROUND: Primary malignant brain tumours are more than one-third of all brain tumours and despite the molecular investigation to identify cancer driver mutations, the current therapeutic options available are challenging due to high intratumour heterogeneity. In addition, an immunosuppressive and inflammatory tumour microenvironment strengthens cancer progression. Therefore, we defined an immune and inflammatory profiling of meningioma and glial tumours to elucidate the role of the immune infiltration in these cancer types. METHODS: Using tissue microarrays of 158 brain tumour samples, we assessed CD3, CD4, CD8, CD20, CD138, Granzyme B (GzmB), 5-Lipoxygenase (5-LOX), Programmed Death-Ligand 1 (PD-L1), O-6-Methylguanine-DNA Methyltransferase (MGMT) and Transglutaminase 2 (TG2) expression by immunohistochemistry (IHC). IHC results were correlated using a Spearman correlation matrix. Transcript expression, correlation, and overall survival (OS) analyses were evaluated using public datasets available on GEPIA2 in Glioblastoma (GBM) and Lower Grade Glioma (LGG) cohorts. RESULTS: Seven out of ten markers showed a significantly different IHC expression in at least one of the evaluated cohorts whereas CD3, CD4 and 5-LOX were differentially expressed between GBMs and astrocytomas. Correlation matrix analysis revealed that 5-LOX and GzmB expression were associated in both meningiomas and GBMs, whereas 5-LOX expression was significantly and positively correlated to TG2 in both meningioma and astrocytoma cohorts. These findings were confirmed with the correlation analysis of TCGA-GBM and LGG datasets. Profiling of mRNA levels indicated a significant increase in CD3 (CD3D, CD3E), and CD138 (SDC1) expression in GBM compared to control tissues. CD4 and 5-LOX (ALOX5) mRNA levels were significantly more expressed in tumour samples than in normal tissues in both GBM and LGG. In GBM cohort, GzmB (GZMB), SDC1 and MGMT gene expression predicted a poor overall survival (OS). Moreover, in LGG cohort, an increased expression of CD3 (CD3D, CD3E, CD3G), CD8 (CD8A), GZMB, CD20 (MS4A1), SDC1, PD-L1, ALOX5, and TG2 (TGM2) genes was associated with worse OS. CONCLUSIONS: Our data have revealed that there is a positive and significant correlation between the expression of 5-LOX and GzmB, both at RNA and protein level. Further evaluation is needed to understand the interplay of 5-LOX and immune infiltration in glioma progression.

Scenario building model to support the resilience planning of winemaking regions: The case of the Douro territory (Portugal).

Today resilience paradigm is shared by both academic and political debates, and it is gradually being implemented into plans, programmes, and project's initiatives. In this context, wine regions, particularly those designated as UNESCO sites, show their robustness and vulnerabilities as Socio-Ecological Systems. The climate change impact is increasing the exposure of their aesthetic, cultural, economic, natural values to potential losses and therefore an effective response is required To build resilient strategies, Decision Makers are increasingly considering multidimensional models in planning and assessment processes. This paper continues a research work that develops an integrated evaluation framework constituted by Multicriteria Decision Analysis to calculate a Territorial Resilience Index, a dynamical model to predict future ecological scenarios and scenario building to define a resilient strategy for the Douro territory (Portugal). This paper focuses on scenario building which uses specific tools such as Social Network Analysis to identify and investigate the relationships between real actors and stakeholders, Wilson matrix to assess the degree of uncertainty and relevance of the strategies identified by a panel of specialists, and consistency matrix to evaluate the strategies consistency in achieving the Sustainable Development Goals and UNESCO requirements. The obtained protocol of guidelines and recommendations can support Decision Makers in the design of sustainable and resilient transformation, thereby assisting in the preservation of the UNESCO site.

A decision support system for territorial resilience assessment and planning: An application to the Douro Valley (Portugal).

This paper aims to assess the territorial resilience of a socio-ecological system through an innovative integrated evaluation framework to aid the decision-making process in the planning of transformation scenarios. This framework employs a set of resilience indicators through a Multicriteria Decision Analysis (MCDA) coupled with a Lotka-Volterra mathematical model of cooperative type. The set of indicators aims to calculate a composite index of Territorial Resilience (TRI), whereas the mathematical model is an extension of an existing model, aimed to predict possible long-time scenarios. The proposed operational framework for rural and vineyard landscapes aims to bridge the existing gap between territorial resilience theory and practice, with an innovative Decision Support System able to assist Decision Makers and territory planners in the planning and management of resilient territorial systems. This integrated evaluation framework is applied to a famous wine region in Portugal, the Douro Valley, where Port-wine grows. Such framework, especially in a context of adaptive governance, proves to be a suitable support in the field of landscape and urban planning to evaluate the dynamics of socio-ecological systems and to envision long-term policies and actions.

Promoting health equity through social capital in deprived communities: a natural policy experiment in Trieste, Italy.

The Trieste Habitat Micro-area Programme (HMP), an innovative social-health service policy, has offered a natural experiment to empirically evaluate the social mechanisms through which social capital may have an impact on health inequalities. To date, literature clarifying this causal chain is scanty. This empirical study tested the following hypotheses: H1) innovative social-health practices can activate social mechanisms intentionally and systematically so as to generate social capital; H2) such social mechanisms increase specific properties of social capital, in particular those influencing more vulnerable individuals' relationships; H3) investing in these properties can enhance capabilities and, consequently, control over the health of more vulnerable individuals. The study was carried out during 2016-2018 and used both qualitative and quantitative methods. The qualitative part investigated the field experience of the HMP through interviews, focus groups and workshops with HMP professionals. The quantitative part assessed the effect HMP might have on these properties and the capacity to face health risks of more vulnerable individuals. Three samples, each of 200 individuals, residing in the target and in control areas were interviewed using a semi-structured questionnaire. One control sample was matched to the 200 treated subjects using a Propensity Score Matching. The results of the study suggest that the HMP intervention stimulated the development of empowerment, collaboration and interdependence among vulnerable people. This produced an increase in their social capital under several aspects, including enhanced trust, network extension and participation, cooperation and reciprocal help with neighbours, as well as improving their judgement on quality, timing and efficacy of the help received from institutions, relatives or friends. These findings show that socially shared relationships can create innovative local models of a universalistic generative welfare system, which would be both inclusive and able to enhance individual capabilities. These models could be disseminated and carried over to other contexts.

[Epidemiology in support of intervention priorities: the case of diabetes in Turin (Piedmont Region, Northern Italy)]. / L'epidemiologia a supporto delle priorità di intervento: il caso del diabete a Torino.

OBJECTIVES: to describe the epidemiology of diabetes within the city of Turin (Piedmont Region, Northern Italy) and to present the process initiated by the city network of diabetes care for the improvement of prevention and treatment of the disease. DESIGN: ecological study based on administrative database. SETTING AND PARTICIPANTS: residents in Turin from 2016 to 2018. MAIN OUTCOME MEASURES: incidence and prevalence of diabetes, percentage of glycosylated haemoglobin testing, and case-fatality. RESULTS: in the considered three-year period (2016-2018), the cumulative incidence of diabetes was 11.5 x1,000; as of 31.12.2018 the prevalence was 5.9%. 77% had performed at least one measurement of glycated haemoglobin during the previous year, and the case-fatality was 12.6% in the three-year period. The standardized prevalence per statistical zone varied from a minimum of 2% (95%CI 1.2-3.3) to a maximum of 10.2% (95%CI 9.1-11.4). The highest values were recorded in the most deprived city areas. The geographical distribution of incidence, varying between 5.1 x1,000 (95%CI 2.7-10.0) e 19.4 x1,000 (95%CI 15.8-24.0), reproduces the geography of prevalence, as well as the percentage of measurement of glycated haemoglobin, while the variability of the fatality rate is more modest without an obvious geographic pattern. CONCLUSIONS: diabetes occurs most frequently in the most deprived areas of the city, but the response of the health care system is adequate and equitable. Sharing of these results with the city health authorities and the diabetologists has led to identify as a priority interventions for the reduction of unhealthy behaviours, and for the improvements of patient care pathway, starting form the most disadvantaged areas of the city. A process of listening and involvement of all actors potentially interested in the prevention and treatment of diabetes has been started.

Analysis of CCDC6 as a novel biomarker for the clinical use of PARP1 inhibitors in malignant pleural mesothelioma.

OBJECTIVES: CCDC6 (coiled-coil domain containing 6) is a player of the HR response to DNA damage and has been predicted to interact with BAP1, another HR-DNA repair gene highly mutated in Malignant Pleural Mesothelioma (MPM), an aggressive cancer with poor prognosis. CCDC6 levels are modulated by the deubiquitinase USP7, and CCDC6 defects have been reported in several tumors determining PARP-inhibitors sensitivity. Our aim was to investigate the functional role of CCDC6 in MPM carcinogenesis and response to PARP-inhibitors. MATERIALS AND METHODS: The interaction between CCDC6 and BAP1 was confirmed in MPM cells, by co-immunoprecipitation. Upon USP7 inhibition, that induces CCDC6 degradation, the ability to repair the DSBs and the sensitivity to PARP inhibitors, was explored by HR reporter and by cells viability assays, respectively. A TMA including 34 MPM cores was immunostained for CCDC6, USP7 and BAP1 and the results correlated by statistical analysis. RESULTS: MPM cells depleted of CCDC6 showed defects in DSBs repair and sensitivity to PARP inhibitors. The silencing of CCDC6 when combined with the overexpression of BAP1-mutant (Δ221-238) enhanced the HR-DNA repair defects and the PARP inhibitors sensitivity. In the TMA of MPM primary samples, the staining of CCDC6 and of its de-ubiquitinase USP7 showed a significant correlation in the tested primary samples (p = 0.01). CCDC6 was barely detected in 30% of the tumors that also carried BAP1 defects. CONCLUSION: The combination of CCDC6 and BAP1 staining may indicate therapeutic options for DDR targeting, acting in synergism with cisplatinum.

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study.

BACKGROUND: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. METHODS: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. RESULTS: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. CONCLUSIONS: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Association between low lean mass and low bone mineral density in 653 women with hip fracture: does the definition of low lean mass matter?

BACKGROUND AND AIMS: Loss of both muscle and bone mass results in fragility fractures with increased risk of disability, poor quality of life, and death. Our aim was to assess the association between low appendicular lean mass (aLM) defined according to different criteria and low bone mineral density (BMD) in hip-fracture women. METHODS: Six hundred fifty-three women admitted to our rehabilitation hospital underwent dual energy X-ray absorptiometry 19.1 ± 4.1 (mean ± SD) days after hip-fracture occurrence. Low aLM was identified according to either Baumgartner's definition (aLM/height2 less than two standard deviations below the mean of the young reference group) or FNIH criteria: aLM <15.02 kg, or aLM adjusted for body mass index (BMI) <0.512. Low BMD was diagnosed with a T-score <-2.5 at the unfractured femoral neck. RESULTS: Using Baumgartner's definition, the association between low aLM/height2 and low BMD was significant: χ 2(1, n = 653) = 8.52 (p = 0.004), but it was erased by adjustments for age and fat mass. Using the FNIH definition the association between low aLM and low BMD was significant: χ 2(1, n = 653) = 42.5 (p < 0.001), and it was confirmed after adjustment for age and fat mass (p < 0.001). With the FNIH definition based on aLM/BMI ratio the association between low aLM/BMI ratio and low BMD was nonsignificant: χ 2(1, n = 653) = 0.003 (p = 0.957). CONCLUSIONS: The association between low aLM and low BMD in women with hip fracture dramatically depends on the adopted definition of low aLM. FNIH threshold for aLM (<15.02 kg) emerges as a useful tool to capture women with damage of the muscle-bone unit.

USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs.

OBJECTIVES: CCDC6 gene product is a tumor-suppressor pro-apoptotic protein, substrate of ATM, involved in DNA damage response and repair. Altered levels of CCDC6 expression are dependent on post-translational modifications, being the de-ubiquitinating enzyme USP7 responsible of the fine tuning of the CCDC6 stability. Thus, our aim was to investigate CCDC6 and USP7 expression levels in Lung-Neuroendocrine Tumors (L-NETs) to verify if they correlate and may be exploited as novel predictive therapeutic markers. MATERIALS AND METHODS: Tumor tissues from 29 L-NET patients were investigated on tissue microarrays. CCDC6 levels were scored and correlated with immunoreactivity for USP7. Next generation sequencing (NGS) of a homogenous group of Large Cell Neuroendocrine Carcinoma (LCNEC) (N=8) was performed by Ion AmpliSeq NGS platform and the Ion AmpliSeq Cancer Hotspot Panel v2. The inhibition of USP7, using P5091, was assayed in vitro to accelerate CCDC6 turnover in order to sensitize the neuroendocrine cancer cells to PARP-inhibitors, alone or in association with cisplatinum. RESULTS: The immunostaining of 29 primary L-NETs showed that the intensity of CCDC6 staining correlated with the levels of USP7 expression (p≤0.05). The NGS analysis of 8 LCNEC revealed mutations in the hot spot regions of the p53 gene (in 6 out of 8). Moreover, gene polymorphisms were identified in the druggable STK11, MET and ALK genes. High intensity of p53 immunostaining was reported in the 6 tissues carrying the TP53 mutations. The inhibition of USP7 by P5091 accelerated the degradation of CCDC6 versus control in cycloheximide treated L-NET cells in vitro and sensitized the cells to PARP-inhibitors alone and in combination with cisplatinum. CONCLUSION: Our data suggest that CCDC6 and USP7 have a predictive value for the clinical usage of USP7 inhibitors in combination with the PARP-inhibitors in L-NET in addition to standard therapy.

Engineering double-well potentials with variable-width annular Josephson tunnel junctions.

Long Josephson tunnel junctions are non-linear transmission lines that allow propagation of current vortices (fluxons) and electromagnetic waves and are used in various applications within superconductive electronics. Recently, the Josephson vortex has been proposed as a new superconducting qubit. We describe a simple method to create a double-well potential for an individual fluxon trapped in a long elliptic annular Josephson tunnel junction characterized by an intrinsic non-uniform width. The distance between the potential wells and the height of the inter-well potential barrier are controlled by the strength of an in-plane magnetic field. The manipulation of the vortex states can be achieved by applying a proper current ramp across the junction. The read-out of the state is accomplished by measuring the vortex depinning current in a small magnetic field. An accurate one-dimensional sine-Gordon model for this strongly non-linear system is presented, from which we calculate the position-dependent fluxon rest-mass, its Hamiltonian density and the corresponding trajectories in the phase space. We examine the dependence of the potential properties on the annulus eccentricity and its electrical parameters and address the requirements for observing quantum-mechanical effects, as discrete energy levels and tunneling, in this two-state system.

Prevalence and burden of vertebral fractures in older men and women with hip fracture: A cross-sectional study.

AIM: To investigate the prevalence and burden (combination of number and severity) of vertebral fractures in men and women with hip fracture. METHODS: We investigated 458 of 490 hip-fracture patients admitted consecutively to a rehabilitation hospital. Lateral radiographs of the spine were taken 19.2 ± 5.5 days (mean ± SD) after hip-fracture occurrence. To obtain a summary measure of vertebral fracture burden, we calculated the spinal deformity index (SDI) by summing the fracture grades assessed using Genant's method of all vertebrae (T4 to L4). RESULTS: The median SDI score was 2 in both the 411 women and the 47 men (interquartile range 0-4 in both groups), and no significant between-sex differences were found (P = 0.52). A total of 69% of the women (95% CI 65-74%), and 60% of the men (95% CI 45-74%) had at least one mild vertebral fracture (SDI score ≥1), 41% of the women (95% CI 36-46%) and 38% of the men (95% CI 24-53%) had a SDI score ≥3, whereas 16% of the women (95% CI 12% 19%) and 17% of the men (95%CI 6-28%) had at least one severe vertebral fracture. Sex was not significantly associated with a SDI score ≥1, or ≥3 or with the presence of at least one severe vertebral fracture after adjustment for age, hip-fracture type, cognitive impairment, pressure ulcers, neurological impairment, comorbidities, number of medications in use and Barthel index scores. CONCLUSIONS: The prevalence of vertebral fractures was high after hip fracture in both men and women. We found no significant between-sex differences in the prevalence and burden of vertebral fractures.

Time trend 2000-2013 of vitamin D status in older people who sustain hip fractures: steps forward or steps back? A retrospective study of 1599 patients.

BACKGROUND: Substantial proportions of hip-fracture patients have very low serum levels of 25-hydroxyvitamin D, which can negatively affect rehabilitation. However, it is not known whether changes in vitamin D deficiency have occurred over the last years in the patients who sustain hip fractures. AIM: To assess time trend 2000-2013 of calcifediol serum levels in the hip-fracture patients admitted to our rehabilitation division. DESIGN: Retrospective observational study. SETTING: A rehabilitation hospital division. POPULATION: A number of 1599 inpatients with a hip fracture admitted between January 1, 2000 and December 31, 2013 to our rehabilitation division. METHODS: A blood sample was collected in the morning following an overnight fasting 14.4±4.4 (mean±SD) days after surgery. We assessed 25-hydroxyvitamin D levels by an immunoenzymatic assay. RESULTS: Calcifediol levels increased till 2006-2007 and decreased afterward. In 2006-2007, the median 25-hydroxyvitamin D level (13.1 ng/mL, interquartile range 7.9-25ng/mL) was significantly higher (P<0.001) than the one found in both the periods 2000-2001 (5.4 ng/mL, interquartile range 3.5-9 ng/mL), and 2012-2013 (7ng/mL, interquartile range 5-14 ng/mL). In the last two-year period of observation (2012-2013), 25-hydroxyvitamin D levels were slightly higher (P<0.001) than in the first one (2000-2001). The association between periods of observation and 25-hydroxyvitamin D levels persisted after adjustment for age, BMI, and sex (P<0.001). CONCLUSIONS: A significant increase in calcifediol concentrations was seen till 2006-2007, but a significant decrease was observed afterward. Finally, calcifediol levels were only slightly higher in the last two years of observation than in the first two years and severe vitamin D deficiency was common during the whole 14-year study period. CLINICAL REHABILITATION IMPACT: Heightened awareness is needed to prevent and treat vitamin D deficiency in hip-fracture patients.

Expression and potential role of the peptide orexin-A in prostate cancer.

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A in human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer.

FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC.

CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response.Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.

Presarcopenia and sarcopenia in hip-fracture women: prevalence and association with ability to function in activities of daily living.

BACKGROUND AND AIMS: Sarcopenia staging systems have been proposed, but little is known on their application in hip-fracture patients. Our aim was to assess the prevalence of presarcopenia and sarcopenia and their association with ability to function in activities of daily living in hip-fracture women. METHODS: We investigated white women (N = 138 of 149) who were consecutively admitted to a rehabilitation hospital because of their first hip fracture. In each woman, we measured appendicular lean mass (aLM) by dual-energy X-ray absorptiometry, at a median of 18 days after hip fracture occurrence. On the same day, we assessed grip strength with a handheld dynamometer. Functional autonomy was assessed by the Barthel Index. We used the European Working Group on Sarcopenia in Older People (EWGSOP) definition to calculate the prevalence of presarcopenia and sarcopenia, taking into account both aLM/height(2) and handgrip strength. Gait speed was not considered, because of the recent hip fracture. RESULTS: Twenty-three (17 %) of the 138 women fulfilled the diagnostic criteria for presarcopenia whereas 80 (58 %) were sarcopenic. The women with presarcopenia were younger, healthier and with higher Barthel Index scores (median 65 vs. 55; interquartile range 60-75 and 50-60, respectively; p < 0.001) than those with sarcopenia. Significant differences in Barthel Index scores at the time of assessment (but not at the end of the rehabilitation course) persisted after multiple adjustments (p < 0.001). CONCLUSIONS: The prevalence of presarcopenia and sarcopenia was high in hip-fracture women. Presarcopenic women had higher ability to function in activities of daily living than sarcopenic women.

New therapeutic perspectives in CCDC6 deficient lung cancer cells.

Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p ≤ 0.02) and negatively correlated to the disease free survival (p ≤ 0.01) and the overall survival (p ≤ 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

Concomitant upper limb fractures and short-term functional recovery in hip fracture patients: does the site of upper limb injury matter?

OBJECTIVE: The aim of this study was to evaluate functional recovery in a subgroup of hip fracture patients who sustained a simultaneous fracture at the upper limb, taking into account the site of upper limb injury. DESIGN: Of 760 patients admitted consecutively to the authors' rehabilitation hospital because of a fall-related hip fracture, 700 were retrospectively investigated. Functional outcome was assessed using Barthel Index scores. RESULTS: In 49 of the 700 patients, a single fall resulted in both a hip fracture and a fracture of either wrist (n = 34) or proximal humerus (n = 15). The patients with concomitant shoulder fractures had lower median Barthel Index scores after rehabilitation (70 vs. 90, P = 0.003), lower median Barthel Index effectiveness (57.1 vs. 76.9, P = 0.018), and prolonged median length of stay (42 vs. 36 days, P = 0.011) than did the patients with isolated hip fractures. Significant differences persisted after adjustment for six potential confounders. The adjusted odds ratio for achieving a Barthel Index score lower than 85 was 6.71 (95% confidence interval, 1.68-26.81; P = 0.007) for the patients with concomitant shoulder fractures. Conversely, no prognostic disadvantages were associated with concomitant wrist fractures. CONCLUSIONS: Data show a worse functional recovery and a prolonged length of stay in the subgroup of hip fracture patients who sustained a concomitant fracture at the proximal humerus, but not at the wrist.

Handgrip strength but not appendicular lean mass is an independent predictor of functional outcome in hip-fracture women: a short-term prospective study.

OBJECTIVE: To investigate the contribution of muscle mass and handgrip strength in predicting the functional outcome after hip fracture in women. DESIGN: Observational study. SETTING: Rehabilitation hospital. PARTICIPANTS: White women (N=123 of 149) who were consecutively admitted to a rehabilitation hospital because of their first fracture of the hip. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured appendicular lean mass (aLM) by dual-energy x-ray absorptiometry (DXA) 21.1 ± 8.7 (mean ± SD) days after hip fracture occurrence in the 123 women. On the same day, we assessed grip strength at the nondominant arm with a dynamometer. At the end of acute inpatient rehabilitation we measured the ability to function in activities of daily living by using the Barthel Index, and lower limb performance by using the Timed Up and Go (TUG) test. RESULTS: We found significant correlations between handgrip strength measured before rehabilitation and Barthel Index scores after rehabilitation (ρ=.50; P<.001), Barthel Index effectiveness (ρ=.45; P<.001), and the TUG test (ρ=-.41; P<.001). Conversely, we found no significant correlations between aLM/height(2) and Barthel Index scores after rehabilitation (ρ=.075; P=.41), Barthel Index effectiveness (ρ=.06; P=.53), or the TUG test (ρ=.005; P=.96). Significant associations between grip strength and all the outcome measures persisted after adjustment for 8 potential confounders, including Barthel Index scores before rehabilitation, age, number of medications, number of comorbidities, pressure ulcers, concomitant infections, time between fracture occurrence and assessment, and aLM/height(2). CONCLUSIONS: Grip strength, but not DXA-assessed aLM, significantly predicted short-term functional outcome in women after a hip fracture.