Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients’ genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/2/jbm410377_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/1/jbm410377.pd

Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice

Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss

The prevalence of obesity has continued to rise over the past three decades leading to significant increases in obesity-related medical care costs from metabolic and non-metabolic sequelae. It is now clear that expansion of body fat leads to an increase in inflammation with systemic effects on metabolism. In mouse models of diet-induced obesity there is also an expansion of bone marrow adipocytes. However, the persistence of these changes after weight-loss has not been well described. The objective of this study was to investigate the impact of high-fat diet (HFD) and subsequent weight-loss on skeletal parameters in C57Bl6/J mice. Male mice were given a normal chow diet (ND) or 60% HFD at 6-weeks of age for 12-, 16-, or 20-weeks. A third group of mice was put on HFD for 12-weeks and then on ND for 8-weeks to mimic weight-loss. After these dietary challenges the tibia and femur were removed and analyzed by microCT for bone morphology. Decalcification followed by osmium staining was used to assess bone marrow adiposity and mechanical testing was performed to assess bone strength. After 12-, 16-, or 20-weeks of HFD, mice had significant weight gain relative to controls. Body mass returned to normal after weight-loss. Marrow adipose tissue (MAT) volume in the tibia increased after 16-weeks of HFD and persisted in the 20-week HFD group. Weight loss prevented HFD-induced MAT expansion. Trabecular bone volume fraction, mineral content, and number were decreased after 12-, 16-, or 20-weeks of HFD, relative to ND controls, with only partial recovery after weight-loss. Mechanical testing demonstrated decreased fracture resistance after 20-weeks of HFD. Loss of mechanical integrity did not recover after weight-loss. Our study demonstrates that HFD causes long-term, persistent changes in bone quality, despite prevention of marrow adipose tissue accumulation, as demonstrated through changes in bone morphology and mechanical strength in a mouse model of diet-induced obesity and weight-loss

Mortality after the First Diagnosis of Schizophrenia-Spectrum Disorders: A Population-based Retrospective Cohort Study

There is emerging evidence of high mortality rates after the first diagnosis of psychotic disorder. The objective of this study was to estimate the standardized mortality ratio (SMR) in a population-based cohort of individuals with a first diagnosis of schizophrenia-spectrum psychotic disorder (SSD). The cohort included a population-based sample of individuals with a first diagnosis of SSD based on the first diagnosis occurring during hospitalization or in an outpatient setting between 2007 and 2010 in Ontario, Canada. All patients were followed for 5 years after the first diagnosis. The primary outcome was SMR, including all-cause, suicide-related, accidental, and other causes. Between 2007 and 2010, there were 2382 patients in the hospitalization cohort and 11 003 patients in the outpatient cohort. Over the 5-year observation period, 97 (4.1%) of the hospitalization cohort and 292 (2.7%) of the outpatient cohort died, resulting in an SMR of 13.6 and 9.1, respectively. In both cohorts, suicide was the most common cause of death. Approximately 1 in 25 patients with a first diagnosis of SSD during hospitalization, and 1 in 40 patients with a first diagnosis of SSD in an outpatient setting, died within 5 years of first diagnosis in Ontario, Canada. This mortality rate is between 9 and 13 times higher than would be expected in the age-matched general population. Based on these data, timely access to services should be a public health priority to reduce mortality following a first diagnosis of an SSD

Lifeworld Inc. : and what to do about it

Can we detect changes in the way that the world turns up as they turn up? This paper makes such an attempt. The first part of the paper argues that a wide-ranging change is occurring in the ontological preconditions of Euro-American cultures, based in reworking what and how an event is produced. Driven by the security – entertainment complex, the aim is to mass produce phenomenological encounter: Lifeworld Inc as I call it. Swimming in a sea of data, such an aim requires the construction of just enough authenticity over and over again. In the second part of the paper, I go on to argue that this new world requires a different kind of social science, one that is experimental in its orientation—just as Lifeworld Inc is—but with a mission to provoke awareness in untoward ways in order to produce new means of association. Only thus, or so I argue, can social science add to the world we are now beginning to live in

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial.

BACKGROUND: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting. METHODS: Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required. RESULTS: From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively. CONCLUSION: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance

Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

This review summarizes some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for the treatment of metastatic breast cancer patients

Phase i trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

BACKGROUND: This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective secondgeneration inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours. METHODS: In all, 49 patients received axitinib 5mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5mg b.i.d. with paclitaxel/carboplatin. RESULTS: Two patients experienced dose-limiting toxicities: febrile neutropenia (n¼1) in the paclitaxel/carboplatin cohort and fatigue (n¼1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No gradeX3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n¼27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n¼21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination. CONCLUSION: Axitinib 5mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.This study was sponsored by Pfizer Inc. Support was provided in part by National Institutes of Health grant P30 CA006927 to the Fox Chase Cancer Center. We thank the patients who participated in this study and the physicians who referred them, as well as the study coordinators and data managers, Shelley Mayfield and Carol Martins at Pfizer Inc. for support of the study conduct, and Gamal ElSawah, Pfizer Medical Affairs, for his review of the manuscript. Medical writing support was provided by Joanna Bloom, of UBC Scientific Solutions (Southport, CT, USA) and Christine Arris at ACUMED (Tytherington, UK) and was funded by Pfizer In

Safety and Efficacy of Combining Sunitinib with Bevacizumab + Paclitaxel/Carboplatin in Non-small Cell Lung Cancer

Bevacizumab (B) improves survival of patients with metastatic, nonsquamous non-small cell lung cancer. Based on encouraging results from preclinical studies combining B with sunitinib (S), a phase II, randomized, open-label study (Study Assessing the Blockade of both VEGF Receptor and ligand to enhance Efficacy in Lung) was initiated to assess clinical outcomes of adding S to paclitaxel (P)/carboplatin (C) + B (PCB) for first-line treatment of locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer.Study enrollment was to occur in three phases. In the first phase, patients received PC + B (15 mg/kg every 3 weeks), ±S (25 mg daily, 2 weeks on, 1 week off). If tolerated, the second phase would include a third cohort receiving 37.5 mg S. The third phase would consist of PCB ± highest tolerable dose S.Between March 2007 and January 2008, 26 patients were randomized to receive PCB and 30 to PCB + S 25 mg. Because of poor tolerability, none of the patients were escalated to 37.5 mg S. Median treatment duration was 10.3 weeks for PCB and 6.0 weeks for PCB + S. Thirty-five percent of patients on PCB + S required S dose reduction, 52% required S treatment interruption, and 59% discontinued S because of adverse events, most frequently hematologic events (neutropenia, thrombocytopenia, and leukopenia) and fatigue. Patients receiving PCB + S required more B interruptions (38% versus 19% for PCB) and discontinuation (52% versus 35%) because of adverse events. Survival data were limited by small sample sizes and limited treatment duration. Overall survival was not mature at time of analysis: median 6.6 months for PCB + S and not reached for PCB. Two out of 25 efficacy-evaluable patients randomized to the PCB + S cohort had confirmed partial responses, compared with 5 of 19 randomized to the PCB cohort.The addition of S to PCB was not well tolerated because of toxicities. This combination should not be studied further at these doses and schedules

Fluorescent Risedronate Analogues Reveal Bisphosphonate Uptake by Bone Marrow Monocytes and Localization Around Osteocytes In Vivo

Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647–labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Researc