Image-guided patient-specific optimization of catheter placement for convection-enhanced nanoparticle delivery in recurrent glioblastoma.

BACKGROUND: Proper catheter placement for convection-enhanced delivery (CED) is required to maximize tumor coverage and minimize exposure to healthy tissue. We developed an image-based model to patient-specifically optimize the catheter placement for rhenium-186 (186Re)-nanoliposomes (RNL) delivery to treat recurrent glioblastoma (rGBM). METHODS: The model consists of the 1) fluid fields generated via catheter infusion, 2) dynamic transport of RNL, and 3) transforming RNL concentration to the SPECT signal. Patient-specific tissue geometries were assigned from pre-delivery MRIs. Model parameters were personalized with either 1) individual-based calibration with longitudinal SPECT images, or 2) population-based assignment via leave-one-out cross-validation. The concordance correlation coefficient (CCC) was used to quantify the agreement between the predicted and measured SPECT signals. The model was then used to simulate RNL distributions from a range of catheter placements, resulting in a ratio of the cumulative RNL dose outside versus inside the tumor, the "off-target ratio" (OTR). Optimal catheter placement) was identified by minimizing OTR. RESULTS: Fifteen patients with rGBM from a Phase I/II clinical trial (NCT01906385) were recruited to the study. Our model, with either individual-calibrated or population-assigned parameters, achieved high accuracy (CCC > 0.80) for predicting RNL distributions up to 24 h after delivery. The optimal catheter placements identified using this model achieved a median (range) of 34.56 % (14.70 %-61.12 %) reduction on OTR at the 24 h post-delivery in comparison to the original placements. CONCLUSIONS: Our image-guided model achieved high accuracy for predicting patient-specific RNL distributions and indicates value for optimizing catheter placement for CED of radiolabeled liposomes.

A Pilot Study on Patient-specific Computational Forecasting of Prostate Cancer Growth during Active Surveillance Using an Imaging-informed Biomechanistic Model.

Active surveillance (AS) is a suitable management option for newly diagnosed prostate cancer, which usually presents low to intermediate clinical risk. Patients enrolled in AS have their tumor monitored via longitudinal multiparametric MRI (mpMRI), PSA tests, and biopsies. Hence, treatment is prescribed when these tests identify progression to higher-risk prostate cancer. However, current AS protocols rely on detecting tumor progression through direct observation according to population-based monitoring strategies. This approach limits the design of patient-specific AS plans and may delay the detection of tumor progression. Here, we present a pilot study to address these issues by leveraging personalized computational predictions of prostate cancer growth. Our forecasts are obtained with a spatiotemporal biomechanistic model informed by patient-specific longitudinal mpMRI data (T2-weighted MRI and apparent diffusion coefficient maps from diffusion-weighted MRI). Our results show that our technology can represent and forecast the global tumor burden for individual patients, achieving concordance correlation coefficients from 0.93 to 0.99 across our cohort (n = 7). In addition, we identify a model-based biomarker of higher-risk prostate cancer: the mean proliferation activity of the tumor (P = 0.041). Using logistic regression, we construct a prostate cancer risk classifier based on this biomarker that achieves an area under the ROC curve of 0.83. We further show that coupling our tumor forecasts with this prostate cancer risk classifier enables the early identification of prostate cancer progression to higher-risk disease by more than 1 year. Thus, we posit that our predictive technology constitutes a promising clinical decision-making tool to design personalized AS plans for patients with prostate cancer. SIGNIFICANCE: Personalization of a biomechanistic model of prostate cancer with mpMRI data enables the prediction of tumor progression, thereby showing promise to guide clinical decision-making during AS for each individual patient.

Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors.

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days' supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher's tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p<.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p<.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Early anteroposterior regionalisation of human neural crest is shaped by a pro-mesodermal factor.

The neural crest (NC) is an important multipotent embryonic cell population and its impaired specification leads to various developmental defects, often in an anteroposterior (A-P) axial level-specific manner. The mechanisms underlying the correct A-P regionalisation of human NC cells remain elusive. Recent studies have indicated that trunk NC cells, the presumed precursors of childhood tumour neuroblastoma, are derived from neuromesodermal-potent progenitors of the postcranial body. Here we employ human embryonic stem cell differentiation to define how neuromesodermal progenitor (NMP)-derived NC cells acquire a posterior axial identity. We show that TBXT, a pro-mesodermal transcription factor, mediates early posterior NC/spinal cord regionalisation together with WNT signalling effectors. This occurs by TBXT-driven chromatin remodelling via its binding in key enhancers within HOX gene clusters and other posterior regulator-associated loci. This initial posteriorisation event is succeeded by a second phase of trunk HOX gene control that marks the differentiation of NMPs toward their TBXT-negative NC/spinal cord derivatives and relies predominantly on FGF signalling. Our work reveals a previously unknown role of TBXT in influencing posterior NC fate and points to the existence of temporally discrete, cell type-dependent modes of posterior axial identity control.

Cholesterol supports bovine granulosa cell inflammatory responses to lipopolysaccharide.

In brief: Bovine granulosa cells need to be cultured with serum to generate inflammation in response to bacterial lipopolysaccharide. This study shows that it is cholesterol that facilitates this lipopolysaccharide-stimulated cytokine secretion. Abstract: During bacterial infections of the bovine uterus or mammary gland, ovarian granulosa cells mount inflammatory responses to lipopolysaccharide (LPS). In vitro, LPS stimulates granulosa cell secretion of the cytokines IL-1α and IL-1ß and the chemokine IL-8. These LPS-stimulated inflammatory responses depend on culturing granulosa cells with serum, but the mechanism is unclear. Here, we tested the hypothesis that cholesterol supports inflammatory responses to LPS in bovine granulosa cells. We used granulosa cells isolated from 4 to 8 mm and >8.5 mm diameter ovarian follicles and manipulated the availability of cholesterol. We found that serum or follicular fluid containing cholesterol increased LPS-stimulated secretion of IL-1α and IL-1ß from granulosa cells. Conversely, depleting cholesterol using methyl-ß-cyclodextrin diminished LPS-stimulated secretion of IL-1α, IL-1ß and IL-8 from granulosa cells cultured in serum. Follicular fluid contained more high-density lipoprotein cholesterol than low-density lipoprotein cholesterol, and granulosa cells expressed the receptor for high-density lipoprotein, scavenger receptor class B member 1 (SCARB1). Furthermore, culturing granulosa cells with high-density lipoprotein cholesterol, but not low-density lipoprotein or very low-density lipoprotein cholesterol, increased LPS-stimulated inflammation in granulosa cells. Cholesterol biosynthesis also played a role in granulosa cell inflammation because RNAi of mevalonate pathway enzymes inhibited LPS-stimulated inflammation. Finally, treatment with follicle-stimulating hormone, but not luteinising hormone, increased LPS-stimulated granulosa cell inflammation, and follicle-stimulating hormone increased SCARB1 protein. However, changes in inflammation were not associated with changes in oestradiol or progesterone secretion. Taken together, these findings imply that cholesterol supports inflammatory responses to LPS in granulosa cells.

Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins.

Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune responses to bacteria. Whether oxysterols also influence the protection of cells against pore-forming toxins is unresolved. Here we tested the hypothesis that oxysterols stimulate the intrinsic protection of epithelial cells against damage caused by cholesterol-dependent cytolysins. We treated epithelial cells with oxysterols and then challenged them with the cholesterol-dependent cytolysin, pyolysin. Treating HeLa cells with 27-hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol, or 7ß-hydroxycholesterol reduced pyolysin-induced leakage of lactate dehydrogenase and reduced pyolysin-induced cytolysis. Specifically, treatment with 10 ng/ml 27-hydroxycholesterol for 24 h reduced pyolysin-induced lactate dehydrogenase leakage by 88%, and reduced cytolysis from 74% to 1%. Treating HeLa cells with 27-hydroxycholesterol also reduced pyolysin-induced leakage of potassium ions, prevented mitogen-activated protein kinase cell stress responses, and limited alterations in the cytoskeleton. Furthermore, 27-hydroxycholesterol reduced pyolysin-induced damage in lung and liver epithelial cells, and protected against the cytolysins streptolysin O and Staphylococcus aureus α-hemolysin. Although oxysterols regulate cellular cholesterol by activating liver X receptors, cytoprotection did not depend on liver X receptors or changes in total cellular cholesterol. However, oxysterol cytoprotection was partially dependent on acyl-CoA:cholesterol acyltransferase (ACAT) reducing accessible cholesterol in cell membranes. Collectively, these findings imply that oxysterols stimulate the intrinsic protection of epithelial cells against pore-forming toxins and may help protect tissues against pathogenic bacteria.

Oxysterols protect bovine endometrial cells against pore-forming toxins from pathogenic bacteria.

Many species of pathogenic bacteria secrete toxins that form pores in mammalian cell membranes. These membrane pores enable the delivery of virulence factors into cells, result in the leakage of molecules that bacteria can use as nutrients, and facilitate pathogen invasion. Inflammatory responses to bacteria are regulated by the side-chain-hydroxycholesterols 27-hydroxycholesterol and 25-hydroxycholesterol, but their effect on the intrinsic protection of cells against pore-forming toxins is unclear. Here, we tested the hypothesis that 27-hydroxycholesterol and 25-hydroxycholesterol help protect cells against pore-forming toxins. We treated bovine endometrial epithelial and stromal cells with 27-hydroxycholesterol or 25-hydroxycholesterol, and then challenged the cells with pyolysin, which is a cholesterol-dependent cytolysin from Trueperella pyogenes that targets these endometrial cells. We found that treatment with 27-hydroxycholesterol or 25-hydroxycholesterol protected both epithelial and stomal cells against pore formation and the damage caused by pyolysin. The oxysterols limited pyolysin-induced leakage of potassium and lactate dehydrogenase from cells, and reduced cytoskeletal changes and cytolysis. This oxysterol cytoprotection against pyolysin was partially dependent on reducing cytolysin-accessible cholesterol in the cell membrane and on activating liver X receptors. Treatment with 27-hydroxycholesterol also protected the endometrial cells against Staphylococcus aureus α-hemolysin. Using mass spectrometry, we found 27-hydroxycholesterol and 25-hydroxycholesterol in uterine and follicular fluid. Furthermore, epithelial cells released additional 25-hydroxycholesterol in response to pyolysin. In conclusion, both 27-hydroxycholesterol and 25-hydroxycholesterol increased the intrinsic protection of bovine endometrial cells against pore-forming toxins. Our findings imply that side-chain-hydroxycholesterols may help defend the endometrium against pathogenic bacteria.

Patient specific, imaging-informed modeling of rhenium-186 nanoliposome delivery via convection-enhanced delivery in glioblastoma multiforme.

Convection-enhanced delivery of rhenium-186 (186Re)-nanoliposomes is a promising approach to provide precise delivery of large localized doses of radiation for patients with recurrent glioblastoma multiforme. Current approaches for treatment planning utilizing convection-enhanced delivery are designed for small molecule drugs and not for larger particles such as186Re-nanoliposomes. To enable the treatment planning for186Re-nanoliposomes delivery, we have developed a computational fluid dynamics approach to predict the distribution of nanoliposomes for individual patients. In this work, we construct, calibrate, and validate a family of computational fluid dynamics models to predict the spatio-temporal distribution of186Re-nanoliposomes within the brain, utilizing patient-specific pre-operative magnetic resonance imaging (MRI) to assign material properties for an advection-diffusion transport model. The model family is calibrated to single photon emission computed tomography (SPECT) images acquired during and after the infusion of186Re-nanoliposomes for five patients enrolled in a Phase I/II trial (NCT Number NCT01906385), and is validated using a leave-one-out bootstrapping methodology for predicting the final distribution of the particles. After calibration, our models are capable of predicting the mid-delivery and final spatial distribution of186Re-nanoliposomes with a Dice value of 0.69 ± 0.18 and a concordance correlation coefficient of 0.88 ± 0.12 (mean ± 95% confidence interval), using only the patient-specific, pre-operative MRI data, and calibrated model parameters from prior patients. These results demonstrate a proof-of-concept for a patient-specific modeling framework, which predicts the spatial distribution of nanoparticles. Further development of this approach could enable optimizing catheter placement for future studies employing convection-enhanced delivery.

Novel Tumor Growth Rate Analysis in the Randomized CLARINET Study Establishes the Efficacy of Lanreotide Depot/Autogel 120 mg with Prolonged Administration in Indolent Neuroendocrine Tumors.

INTRODUCTION: Tumor quantity while receiving cancer therapy is the sum of simultaneous regression of treatment-sensitive and growth of treatment-resistant fractions at constant rates. Exponential rate constants for tumor regression/decay (d) and growth (g) can be estimated. Previous studies established g as a biomarker for overall survival; g increases after treatment cessation, can estimate doubling times, and can assess treatment effectiveness in small cohorts by benchmarking to large reference data sets. Using this approach, we analyzed data from the clinical trial CLARINET, evaluating lanreotide depot/autogel 120 mg/4 weeks (LAN) for treatment of neuroendocrine tumors (NETs). METHODS AND MATERIALS: Computed tomography imaging data from 97 LAN- and 101 placebo-treated patients from CLARINET were analyzed to estimate g and d. RESULTS: Data from 92% of LAN- and 94% of placebo-treated patients could be fit to one of the equations to derive g and d (p < .001 in most data sets). LAN-treated patients demonstrated significantly slower g than placebo recipients (p = .00315), a difference of 389 days in doubling times. No significant difference was observed in d. Over periods of LAN administration up to 700 days, g did not change appreciably. Simulated analysis with g as the endpoint showed a sample size of 48 sufficient to detect a difference in median g with 80% power. CONCLUSION: Although treatment of NETs with LAN can affect tumor shrinkage, LAN primarily slows tumor growth rather than accelerates tumor regression. Evidence of LAN efficacy across tumors was identified. The growth-retarding effect achieved with LAN was sustained for a prolonged period of time. IMPLICATIONS FOR PRACTICE: The only curative treatment for neuroendocrine tumors (NETs) is surgical resection; however, because of frequent late diagnosis, this is often impossible. Because of this, treatment of NETs is challenging and often aims to reduce tumor burden and delay progression. A novel method of analysis was used to examine data from the CLARINET trial, confirming lanreotide depot/autogel is effective at slowing tumor growth and extending progression-free survival. By providing the expected rate and doubling time of tumor growth early in the course of treatment, this method of analysis has the potential to guide physicians in their management of patients with NETs.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Retinoic Acid Accelerates the Specification of Enteric Neural Progenitors from In-Vitro-Derived Neural Crest.

The enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1 and 7. Defects in the development and function of the ENS cause a range of enteric neuropathies, including Hirschsprung disease. Little is known about the signals that specify early ENS progenitors, limiting progress in the generation of enteric neurons from human pluripotent stem cells (hPSCs) to provide tools for disease modeling and regenerative medicine for enteric neuropathies. We describe the efficient and accelerated generation of ENS progenitors from hPSCs, revealing that retinoic acid is critical for the acquisition of vagal axial identity and early ENS progenitor specification. These ENS progenitors generate enteric neurons in vitro and, following in vivo transplantation, achieved long-term colonization of the ENS in adult mice. Thus, hPSC-derived ENS progenitors may provide the basis for cell therapy for defects in the ENS.

Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells.

Human pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death. However, we have found that the extent of DNA replication stress, DNA damage, and consequent aberrant mitoses can be substantially reduced by culturing PSCs in the presence of exogenous nucleosides, resulting in improved survival, clonogenicity, and population growth.

Medical record review of transition to lanreotide following octreotide for neuroendocrine tumors.

BACKGROUND: Octreotide has been used for decades in the United States (US) and Europe to treat patients with advanced neuroendocrine tumors (NETs). Lanreotide was approved in 2014 to improve progression-free survival (PFS) in patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic NETs. Therefore, clinicians and patients may consider sequencing therapy from octreotide to lanreotide. However, current real-world outcomes data on patients who have made this transition is limited. METHODS: We conducted a multicenter, noninterventional, retrospective medical record review of patients with locally advanced or metastatic gastroenteropancreatic NETs (NCT03112694). Included patients had been treated with long-acting octreotide monotherapy for ≥90 days before transitioning to lanreotide monotherapy and continued on lanreotide for ≥90 days. Abstractors entered patient demographic and clinical data into a customized, web-based case report form. We assessed clinically defined PFS and other tumor-related outcomes while patients were treated with lanreotide. Outcomes were analyzed according to level of response at the time of transition from octreotide to lanreotide: progressive disease, nonprogressive disease, or unknown. Statistical analyses were descriptive. Clinically defined PFS and duration of treatment with lanreotide were estimated using the Kaplan-Meier method. RESULTS: Data were abstracted for 91 patients with gastroenteropancreatic NETs who received long-acting octreotide followed by lanreotide at six US based sites. At initial diagnosis, 71.4% of patients had stage IV disease. Small intestine (63.7%) and pancreas (14.3%) were the most common primary tumor sites. Mean [standard deviation (SD)] duration of follow-up from diagnosis was 70.6 (41.3) months. Patients received long-acting octreotide for a mean (SD) of 38.4 (32.8) months. When patients transitioned to lanreotide, 57.1% had nonprogressive disease on octreotide, 30.8% had progressive disease, and the remainder had unknown disease status. The most common reasons for switching from octreotide to lanreotide were progressive disease (22.0%), formulary change (15.4%), and patient preference (9.9%). Patients received lanreotide for a median (95% CI) duration of 24.7 (16.7-59.9) months. At the end of follow-up, 74% of patients remained on lanreotide monotherapy. Progression occurred in 24.2% of patients during lanreotide treatment. Overall median (95% CI) clinician-defined PFS following the transition to lanreotide was estimated to be 23.7 months [20.2 months-NE (not estimable)]. Patients with nonprogressive disease when they transitioned to lanreotide experienced a median clinician-defined PFS of 24.7 (17.0-NE) months. Among patients reported to have progressive disease when they transitioned to lanreotide, median (95% CI) clinician-defined PFS was estimated to be 15.2 (11.4-NE) months. There were no material differences in adverse events recorded during the long-acting octreotide and lanreotide treatment periods. CONCLUSIONS: Our study suggests that lanreotide monotherapy is well tolerated and may contribute to stabilization of disease in a subset of patients with locally advanced or metastatic gastroenteropancreatic NETs previously treated with long-acting octreotide.

Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth.

Prostate cancer and benign prostatic hyperplasia are common genitourinary diseases in aging men. Both pathologies may coexist and share numerous similarities, which have suggested several connections or some interplay between them. However, solid evidence confirming their existence is lacking. Recent studies on extensive series of prostatectomy specimens have shown that tumors originating in larger prostates present favorable pathological features. Hence, large prostates may exert a protective effect against prostate cancer. In this work, we propose a mechanical explanation for this phenomenon. The mechanical stress fields that originate as tumors enlarge have been shown to slow down their dynamics. Benign prostatic hyperplasia contributes to these mechanical stress fields, hence further restraining prostate cancer growth. We derived a tissue-scale, patient-specific mechanically coupled mathematical model to qualitatively investigate the mechanical interaction of prostate cancer and benign prostatic hyperplasia. This model was calibrated by studying the deformation caused by each disease independently. Our simulations show that a history of benign prostatic hyperplasia creates mechanical stress fields in the prostate that impede prostatic tumor growth and limit its invasiveness. The technology presented herein may assist physicians in the clinical management of benign prostate hyperplasia and prostate cancer by predicting pathological outcomes on a tissue-scale, patient-specific basis.

Regenerative Medicine: Advances from Developmental to Degenerative Diseases.

Chronic tissue and organ failure caused by an injury, disease, ageing or congenital defects represents some of the most complex therapeutic challenges and poses a significant financial healthcare burden. Regenerative medicine strategies aim to fulfil the unmet clinical need by restoring the normal tissue function either through stimulating the endogenous tissue repair or by using transplantation strategies to replace the missing or defective cells. Stem cells represent an essential pillar of regenerative medicine efforts as they provide a source of progenitors or differentiated cells for use in cell replacement therapies. Whilst significant leaps have been made in controlling the stem cell fates and differentiating them to cell types of interest, transitioning bespoke cellular products from an academic environment to off-the-shelf clinical treatments brings about a whole new set of challenges which encompass manufacturing, regulatory and funding issues. Notwithstanding the need to resolve such issues before cell replacement therapies can benefit global healthcare, mounting progress in the field has highlighted regenerative medicine as a realistic prospect for treating some of the previously incurable conditions.

Management of pinna haematoma study (MaPHaeS): A multicentre retrospective observational study.

OBJECTIVES: To assess current variation in the management of pinna haematoma (PH) and its effect on outcomes. DESIGN: Multicentre retrospective observational record-based study. SETTING: Eleven hospitals around the UK. PARTICIPANTS: Eighty-three patients above the age of 16 with PH. OUTCOME MEASURES: The primary outcome measure was recurrence rate of PH over a 6-month period post-treatment, assessed by treatment type (scalpel incision vs needle aspiration). Secondary outcome measures assessed the impact of other factors on recurrence, infection and cosmetic complications of PH over a period of 6 months. RESULTS: After adjusting for confounding factors, involvement of the whole ear, and management within an operating theatre were associated with a lower rate of recurrence of pinna haematoma. The drainage technique, suspected aetiology, choice of post-drainage management, grade and specialty of practitioner performing drainage, the use of antibiotic cover and hospital admission did not affect the rate of haematoma recurrence, infection or cosmetic complications. CONCLUSIONS: Where possible PH should be drained in an operating theatre. Multicentre randomized controlled trials are required to further investigate the impact of drainage technique and post-drainage management on outcome.

The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy.

PURPOSE: To explore how follicle-stimulating hormone (FSH) may contribute to cardiovascular, metabolic, skeletal, and cognitive events in men treated for prostate cancer, with various forms of androgen deprivation therapy (ADT). MATERIALS AND METHODS: A colloquium of prostate cancer experts was convened in May 2015, to discuss the role of FSH in the development of unwanted effects associated with ADT. Subsequently, a literature review (Medline, PubMed, and relevant congress abstract databases) was performed to further explore and evaluate the collected evidence. RESULTS: It has become evident that, in the setting of ADT, FSH can promote the development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance. Data also suggest that FSH is an important mediator of bone remodeling, particularly bone resorption, and thereby increases the risk for bone fracture. Additional evidence implicates a role for FSH in bone metastasis as well. The influence of FSH on ADT-induced cognitive deficits awaits further elucidation; however, the possibility that FSH may be involved therein cannot be ruled out. CONCLUSIONS: The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.

Tissue-scale, personalized modeling and simulation of prostate cancer growth.

Recently, mathematical modeling and simulation of diseases and their treatments have enabled the prediction of clinical outcomes and the design of optimal therapies on a personalized (i.e., patient-specific) basis. This new trend in medical research has been termed "predictive medicine." Prostate cancer (PCa) is a major health problem and an ideal candidate to explore tissue-scale, personalized modeling of cancer growth for two main reasons: First, it is a small organ, and, second, tumor growth can be estimated by measuring serum prostate-specific antigen (PSA, a PCa biomarker in blood), which may enable in vivo validation. In this paper, we present a simple continuous model that reproduces the growth patterns of PCa. We use the phase-field method to account for the transformation of healthy cells to cancer cells and use diffusion-reaction equations to compute nutrient consumption and PSA production. To accurately and efficiently compute tumor growth, our simulations leverage isogeometric analysis (IGA). Our model is shown to reproduce a known shape instability from a spheroidal pattern to fingered growth. Results of our computations indicate that such shift is a tumor response to escape starvation, hypoxia, and, eventually, necrosis. Thus, branching enables the tumor to minimize the distance from inner cells to external nutrients, contributing to cancer survival and further development. We have also used our model to perform tissue-scale, personalized simulation of a PCa patient, based on prostatic anatomy extracted from computed tomography images. This simulation shows tumor progression similar to that seen in clinical practice.

Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain.

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-ß (pGSK3ß(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3ß(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system.

Derivation of mesenchymal stromal cells from canine induced pluripotent stem cells by inhibition of the TGFß/activin signaling pathway.

In this study we have generated canine mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, from canine induced pluripotent stem cells (ciPSCs) by small-molecule inhibition of the transforming growth factor beta (TGFß)/activin signaling pathway. These ciPSC-derived MSCs (ciPSC-MSCs) express the MSC markers CD73, CD90, CD105, STRO1, cPDGFRß and cKDR, in addition to the pluripotency factors OCT4, NANOG and REX1. ciPSC-MSCs lack immunostaining for H3K27me3, suggesting that they possess two active X chromosomes. ciPSC-MSCs are highly proliferative and undergo robust differentiation along the osteo-, chondro- and adipogenic pathways, but do not form teratoma-like tissues in vitro. Of further significance for the translational potential of ciPSC-MSCs, we show that these cells can be encapsulated and maintained within injectable hydrogel matrices that, when functionalized with bound pentosan polysulfate, dramatically enhance chondrogenesis and inhibit osteogenesis. The ability to efficiently derive large numbers of highly proliferative canine MSCs from ciPSCs that can be incorporated into injectable, functionalized hydrogels that enhance their differentiation along a desired lineage constitutes an important milestone towards developing an effective MSC-based therapy for osteoarthritis in dogs, but equally provides a model system for assessing the efficacy and safety of analogous approaches for treating human degenerative joint diseases.