Depth effect on point shear wave velocity elastography: Evidence in a chronic hepatitis C patient cohort.

Background and Aims: This study investigated the depth-related bias and the influence of scan plane angle on performance of point-shear-wave elastometry in a chronic hepatitis C patient cohort. Materials and Methods: We included 104 patients affected by chronic liver disease related to the hepatitis C virus. Liver surface nodularity was the reference to diagnose cirrhosis. The ultrasound platform was the Siemens S2000, equipped with point-shear-wave elastometry software. Measurements were obtained in left lateral decubitus from the liver surface to the maximum depth of 8 cm in two orthogonal scan planes according to a standard sampling plane. Scatterplot and box plots explored the depth-related bias graphically. The area under the receiver operating characteristic was used to determine the point-shear-wave elastometry diagnostic performance at progressive depths according to liver surface nodularity. Results: Of the 104 patients, 68 were cirrhotics. Depth-related bias equally modified point-shear-wave elastometry in the two orthogonal scan planes. A better point-shear-wave elastometry diagnostic performance was observed between depths of 4 and 5 cm. The frontal scan plane assured better discrimination between cirrhotic patients and non-cirrhotic patients. Conclusion: Depth is crucial for point-shear-wave elastometry performance. Excellent diagnostic performance at a depth between 4 and 5 cm can also be obtained with a smaller number of measurements than previously recommended.

Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement. Fifty-eight participants received treatment. Total exposure to fedratinib was similar after oral administration of intact capsules or when dispersed in a nutritional supplement (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration geometric mean ratio [AUC0-t GMR] [90% CI], 1.007 [0.929-1.092]). Total exposure to fedratinib was slightly reduced following nasogastric administration (AUC0-t GMR 0.850 [0.802-0.901]) and as a divided dose (AUC0-t GMR 0.836 [0.789-0.886]). No new safety signals were identified for fedratinib, and most participants found the taste and palatability acceptable when dispersed in a nutritional supplement. Overall, results suggest no clinically meaningful differences in total exposure to fedratinib between the tested oral administration methods. These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).

A statistical method for removing unbalanced trials with multiple covariates in meta-analysis.

In meta-analysis literature, there are several checklists describing the procedures necessary to evaluate studies from a qualitative point of view, whereas preliminary quantitative and statistical investigations on the "combinability" of trials have been neglected. Covariate balance is an important prerequisite to conduct meta-analysis. We propose a method to identify unbalanced trials with respect to a set of covariates, in presence of covariate imbalance, namely when the randomized controlled trials generate a meta-sample that cannot satisfy the requisite of randomization/combinability in meta-analysis. The method is able to identify the unbalanced trials, through four stages aimed at achieving combinability. The studies responsible for the imbalance are identified, and then they can be eliminated. The proposed procedure is simple and relies on the combined Anderson-Darling test applied to the Empirical Cumulative Distribution Functions of both experimental and control meta-arms. To illustrate the method in practice, two datasets from well-known meta-analyses in the literature are used.

MRONJ in breast cancer patients under bone modifying agents for cancer treatment-induced bone loss (CTIBL): a multi-hospital-based case series.

BACKGROUND: Cancer treatment-induced bone loss (CTIBL) is the most common adverse event experienced by patients affected by breast cancer (BC) patients, without bone metastases. Bone modifying agents (BMAs) therapy is prescribed for the prevention of CTIBL, but it exposes patients to the risk of MRONJ. METHODS: This multicentre hospital-based retrospective study included consecutive non-metastatic BC patients affected by MRONJ related to exposure to low-dose BMAs for CTIBL prevention. Patients' data were retrospectively collected from the clinical charts of seven recruiting Italian centres. RESULTS: MRONJ lesions were found in fifteen females (mean age 67.5 years), mainly in the mandible (73.3%). The mean duration of BMAs therapy at MRONJ presentation was 34.9 months. The more frequent BMAs was denosumab (53.3%). Ten patients (66.7%) showed the following local risk factors associated to MRONJ development: periodontal disease (PD) in three cases (20%) and the remaining six (40%) have undergone PD-related tooth extractions. One patient presented an implant presence-triggered MRONJ (6.7%). In five patients (33.3%) no local risk factors were observed. CONCLUSIONS: This is the first case series that investigated BC patients under BMAs for CTIBL prevention suffering from MRONJ. These patients seem to have similar probabilities of developing MRONJ as osteo-metabolic ones. Breast cancer patients under BMAs for CTIBL prevention need a regular prevention program for MRONJ, since they may develop bone metastases and be treated with higher doses of BMAs, potentially leading to a high-risk of MRONJ.

Gender and Sex in Medical Practice: An Exploratory Study on Knowledge, Behavior, and Attitude among Sicilian Physicians.

Personalized medicine is a new paradigm in health care, and the concept of socio-cultural gender, as opposed to biological sex, emerged in several medical approaches. This exploratory study aimed to investigate the knowledge of sex and gender in clinical medicine among Sicilian physicians. Data collection was based on an online survey sent to the members of the Medical Councils of Sicily (Italy). The questionnaire included nine specific items about awareness and attitudes regarding gender medicine and its importance in clinical practice. 8023 Sicilian physicians received the solicitation e-mail and only 496 responded. Regarding the knowledge of gender medicine, 71.1% of participants stated that they know it, while 88.5% believe that gender medicine should be included in training programs. Similarly, a high percentage (77.6%) would like to keep up to date on this topic. Physicians sampled seem to understand the importance of gender medicine principles, although their experience of some gender issues (i.e., sex disparities in acute cardiovascular care and smoking cessation strategies) is low (55.44% and 21.57%, respectively). The results of this exploratory study should encourage facing the gender medicine gap in the current curricula of health professionals and should implement the transitional value of sex and gender principles in the clinical setting.

Diagnostic and prognostic value of magnetic resonance imaging in the detection of tumor depth of invasion and bone invasion in patients with oral cavity cancer.

PURPOSE: To evaluate the accuracy of preoperative contrast-enhanced magnetic resonance imaging (MRI) in the assessment of radiological depth of invasion (rDOI) and bone invasion in patients with oral cavity cancer, and the prognostic value of preoperative rDOI. MATERIALS AND METHODS: This retrospective study included patients with surgically resected oral cavity cancer and preoperative MRI acquired within four weeks before surgery. Two readers evaluated the MRI to assess the superficial and deep bone invasion, preoperative T stage, and measured the rDOI. The rDOI was compared to the histopathological DOI (pDOI), used as reference standard. Prognostic value of preoperative features for the disease-specific survival was evaluated using the Kaplan-Meier curve and multivariable Cox proportional hazards analysis. RESULTS: The final population included 80 patients (50 males, mean age 67.7 ± 13.6 years). There was a strong statistically significant correlation between the rDOI (median 10 mm) and the pDOI (median 9 mm) (ρ: 0.978, p < 0.001). The agreement between MRI and histopathological T stage was excellent (k = 0.93, 95% CI 0.86, 0.99). The sensitivity and specificity of preoperative MRI were 93.3% and 98.8% for deep bone invasion, while they were 75.0% and 95.8% for superficial bone invasion, respectively. The rDOI > 10 mm was associated with poorer disease-specific survival (log-rank p = 0.016). The rDOI remained the only independent preoperative predictor associated with poorer disease-specific survival at multivariable analysis (hazard ratio 5.5; 95% CI 1.14, 26.58; p = 0.033). CONCLUSION: Preoperative MRI is accurate for the assessment of DOI and bone invasion. The rDOI is an independent preoperative predictor of disease-specific survival in patients with oral cavity cancer.

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).

An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis.

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor­initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling.

Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.

Detection of pro angiogenic and inflammatory biomarkers in patients with CKD.

Cardiovascular disease (CVD) is the most common cause of death in patients with native and post-transplant chronic kidney disease (CKD). To identify new biomarkers of vascular injury and inflammation, we analyzed the proteome of plasma and circulating extracellular vesicles (EVs) in native and post-transplant CKD patients utilizing an aptamer-based assay. Proteins of angiogenesis were significantly higher in native and post-transplant CKD patients versus healthy controls. Ingenuity pathway analysis (IPA) indicated Ephrin receptor signaling, serine biosynthesis, and transforming growth factor-ß as the top pathways activated in both CKD groups. Pro-inflammatory proteins were significantly higher only in the EVs of native CKD patients. IPA indicated acute phase response signaling, insulin-like growth factor-1, tumor necrosis factor-α, and interleukin-6 pathway activation. These data indicate that pathways of angiogenesis and inflammation are activated in CKD patients' plasma and EVs, respectively. The pathways common in both native and post-transplant CKD may signal similar mechanisms of CVD.

Predicting in-hospital mortality from Coronavirus Disease 2019: A simple validated app for clinical use.

BACKGROUNDS: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19. METHODS AND FINDINGS: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp). CONCLUSIONS: A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19.

Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).

An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. All consecutive hospitalised patients from February 21st to March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included. In-hospital mortality and discharge were evaluated by competing risk analysis. The Fine and Gray model was fitted in order to estimate the effect of covariates on the cumulative incidence functions (CIFs) for in-hospital mortality and discharge. 426 adult patients [median age 68 (IQR 56 to 77 years)] were admitted with confirmed COVID-19 over a 5-week period; 292 (69%) were male. By 21 April 2020, 141 (33%) of these patients had died, 239 (56%) patients had been discharged and 46 (11%) were still hospitalised. Among these 46 patients, updated as of 30 May, 2020, 5 (10.9%) had died, 8 (17.4%) were still in ICU, 12 (26.1%) were transferred to lower intensity care units and 21 (45.7%) were discharged. Regression on the CIFs for in-hospital mortality showed that older age, male sex, number of comorbidities and hospital admission after March 4th were independent risk factors associated with in-hospital mortality. Older age, male sex and number of comorbidities definitively predicted in-hospital mortality in hospitalised patients with COVID-19.

Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis.

Background: An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. Methods: A Markov model was built to simulate overall survival (OS) among patients with advanced HCC. Three first-line (single-agent Sorafenib or Lenvatinib, and combination of Atezolizumab plus Bevacizumab) followed by five second-line treatments (Regorafenib, Cabozantinib, Ramucirumab, Nivolumab, Pembrolizumab) were compared in fifteen sequential strategies. The likelihood of transition between states (initial treatment, cancer progression, death) was derived from clinical trials. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥grade 3) were calculated. The innovative measure, called incremental safety-effectiveness ratio (ISER), of the two best sequential treatments was calculated as the difference in probability of SAEs divided by LYG. Results: Lenvatinib followed by Nivolumab (median OS, 27 months) was the most effective sequence, producing a LYG of 0.75, while Atezolizumab plus Bevacizumab followed by Nivolumab was the safest sequence (SAEs 40%). Accordingly, the net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases. Conclusion: Further sequential clinical trials or large-scale real-world studies may prove useful to evaluate the net health benefit of the best sequential treatment for advanced HCC.

Performance of Radiomics Features in the Quantification of Idiopathic Pulmonary Fibrosis from HRCT.

BACKGROUND: Our study assesses the diagnostic value of different features extracted from high resolution computed tomography (HRCT) images of patients with idiopathic pulmonary fibrosis. These features are investigated over a range of HRCT lung volume measurements (in Hounsfield Units) for which no prior study has yet been published. In particular, we provide a comparison of their diagnostic value at different Hounsfield Unit (HU) thresholds, including corresponding pulmonary functional tests. METHODS: We consider thirty-two patients retrospectively for whom both HRCT examinations and spirometry tests were available. First, we analyse the HRCT histogram to extract quantitative lung fibrosis features. Next, we evaluate the relationship between pulmonary function and the HRCT features at selected HU thresholds, namely -200 HU, 0 HU, and +200 HU. We model the relationship using a Poisson approximation to identify the measure with the highest log-likelihood. RESULTS: Our Poisson models reveal no difference at the -200 and 0 HU thresholds. However, inferential conclusions change at the +200 HU threshold. Among the HRCT features considered, the percentage of normally attenuated lung at -200 HU shows the most significant diagnostic utility. CONCLUSIONS: The percentage of normally attenuated lung can be used together with qualitative HRCT assessment and pulmonary function tests to enhance the idiopathic pulmonary fibrosis (IPF) diagnostic process.

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma.

BACKGROUND: Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods. METHODS: A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan-Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R2. Heterogeneity was explored by meta-regression. RESULTS: We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R2 = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R2 = 0.89, 95%CI 0.78-0.98, and 0.80, 95% CI 0.63-0.96, respectively). Interaction p-values obtained by meta-regression confirmed the robustness of results. CONCLUSIONS: In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.

Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.

Epithelial innate immunity mediates tubular cell senescence after kidney injury.

Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs including kidneys, the accumulation of such cells is a hallmark of aging. We hypothesized that cellular senescence might be induced in the kidney after injury and that this might contribute to progressive organ fibrosis. Testing this hypothesis, we found that tubular epithelial cells (TECs) in mice senesce within a few days of kidney injury and that this response is mediated by epithelial Toll-like and interleukin 1 receptors (TLR/IL-1R) of the innate immune system. Epithelial cell-specific inhibition of innate immune signaling in mice by knockout of myeloid differentiation 88 (Myd88) reduced fibrosis as well as damage to kidney tubules, and also prevented the accumulation of senescent TECs. Importantly, although inactivation of Myd88 after injury ameliorated fibrosis, it did not reduce damage to the tubules. Selectively induced apoptosis of senescent cells by two different approaches only partially reduced kidney fibrosis, without ameliorating damage to the tubules. Our data reveal a cell-autonomous role for epithelial innate immunity in controlling TEC senescence after kidney injury, and additionally suggest that early therapeutic intervention is required for effective reduction of long-term sequelae of AKI.

Prominin-1 controls stem cell activation by orchestrating ciliary dynamics.

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.

Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease.

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II-IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.

ß-Thalassemia heterozygote state detrimentally affects health expectation.

BACKGROUND: Thalassemia minor (Tm) individuals, are generally considered healthy. However, the prognosis of Tm individuals has not been extensively studied. The aim of this study was to evaluate the prognosis of Tm versus controls without ß-thalassemia carrier state. METHODS: A total of 26,006 individuals seeking thalassemia screening at the AOOR Villa Sofia-V. Cervello, Palermo (Italy) were retrospectively studied. Logistic penalised regression model was used to estimate risk of potential complications and survival techniques were used to study mortality. RESULTS: We identified a total of 4943 Tm and 21,063 controls. Tm was associated with significantly higher risks of hospitalisation for cirrhosis (OR 1·94, 95% CI 1·30 to 2·90, p = 0·001), kidney disorders (OR 2·11, 95% CI 1·27 to 3·51, p = 0·004), cholelithiatis (OR 1·39, 95% CI 1·08 to 1·79, p = 0·010), and mood disorders (OR 2·08, 95% CI 1·15 to 3·75, p = 0·015). No statistically difference in life expectancy between thalassemia minor and control group was found (HR 1·090, 95% CI 0·777 to 1·555, p < 0·590; log-rank test p = .426). CONCLUSION: This study shows that Tm affects the prognosis of Tm carriers regarding health expectation. Probably, iron overload and anaemia for several years may be at the basis of these effects.