Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer.

BACKGROUND: Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach. METHODS: A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET. RESULTS: 103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures. CONCLUSION: PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.

The Microbiome as a Modifier of Neurodegenerative Disease Risk.

The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs.

Toward Understanding Microbiome-Neuronal Signaling.

Host-associated microbiomes are emerging as important modifiers of brain activity and behavior. Metabolic, immune, and neuronal pathways are proposed to mediate communication across the so-called microbiota-gut-brain axis. However, strong mechanistic evidence, especially for direct signaling between microbes and sensory neurons, is lacking. Here, we discuss microbial regulation of short-chain fatty acids, neurotransmitters, as-yet-uncharacterized biochemicals, and derivatives of neuromodulatory drugs as important areas for assessing microbial interactions with the nervous system.

Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid-treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.

Pattern of failure in anaplastic glioma patients with an IDH1/2 mutation.

PURPOSE: The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype. METHODS: The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT. RESULTS: A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6­year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p < 0.001). There was a component of local relapse in 63%, of marginal relapse in 19% and of distant relapse in 37% of relapses. Isolated local, marginal and distant relapse was evident in 51, 9 and 22%, respectively. A distant relapse pattern was more frequent in IDHmut compared to IDHwt patients (26% vs. 45%, p = 0.005), especially within the first 2 years post-IMRT. In multivariate analysis, distant relapse remained associated with AAmut (p < 0.002) and delayed IMRT until the second relapse (p < 0.001). CONCLUSION: Although patients with IDH-mutated AG have improved outcomes, there was a higher proportion of distant relapses occurring during the 2 years after IMRT.

Microbiomes as sources of emergent host phenotypes.

Microbial communities associated with animals exert powerful influences on host physiology, regulating metabolism and immune function, as well as complex host behaviors. The importance of host-microbiome interactions for maintaining homeostasis and promoting health raises evolutionarily complicated questions about how animals and their microbiomes have coevolved, and how these relationships affect the ways that animals interact with their environment. Here, we review the literature on the contributions of host factors to microbial community structure and corresponding influences of microbiomes on emergent host phenotypes. We focus in particular on animal behaviors as a basis for understanding potential roles for the microbiome in shaping host neurobiology.

Gs/Gi Regulation of Bone Cell Differentiation: Review and Insights from Engineered Receptors.

G-protein coupled receptors (GPCRs) and their ligands are critical for normal osteoblast formation and function. GPCRs mediate a wide variety of biological processes and are activated by multiple types of extracellular signals, ranging from photons to small molecules to peptides. GPCRs signal through a select number of canonical pathways: the Gs and Gi pathways increase or decrease intracellular cAMP levels, respectively, by acting on adenylate cyclase, while the Gq pathway increases intracellular calcium by activating phospholipase C. In addition, non-canonical GPCR pathways such as ß-arrestin activation are important for osteoblast function. Since many cells express multiple GPCRs, and each individual GPCR may activate multiple signaling pathways, the resulting combinatorial signal provides a mechanism for regulating complex biological processes and effector functions. However, the wide variety of GPCRs, the possibility of multiple receptors acting with signaling redundancy, and the possibility of an individual GPCR activating multiple signaling pathways, also pose challenges for elucidating the role of a particular GPCR. Here, we briefly review the roles of Gs and Gi GPCR signaling in osteoblast function. We describe the successful application of a strategy for directly manipulating the Gs and Gi pathways using engineered receptors. These powerful tools will allow further elucidation of the roles of GPCR signaling in specific lineages of osteoblastic cells, as well as in non-osteoblast cells, all of which remain critical areas of active research.

PTF 11kx: a type Ia supernova with a symbiotic nova progenitor.

There is a consensus that type Ia supernovae (SNe Ia) arise from the thermonuclear explosion of white dwarf stars that accrete matter from a binary companion. However, direct observation of SN Ia progenitors is lacking, and the precise nature of the binary companion remains uncertain. A temporal series of high-resolution optical spectra of the SN Ia PTF 11kx reveals a complex circumstellar environment that provides an unprecedentedly detailed view of the progenitor system. Multiple shells of circumstellar material are detected, and the SN ejecta are seen to interact with circumstellar material starting 59 days after the explosion. These features are best described by a symbiotic nova progenitor, similar to RS Ophiuchi.

Effects of maternal immune activation on gene expression patterns in the fetal brain.

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, ß and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.

Mineral composition is altered by osteoblast expression of an engineered G(s)-coupled receptor.

Activation of the G(s) G protein-coupled receptor Rs1 in osteoblasts increases bone mineral density by 5- to 15-fold in mice and recapitulates histologic aspects of fibrous dysplasia of the bone. However, the effects of constitutive G(s) signaling on bone tissue quality are not known. The goal of this study was to determine bone tissue quality in mice resulting from osteoblast-specific constitutive G(s) activation, by the complementary techniques of FTIR spectroscopy and synchrotron radiation micro-computed tomography (SRµCT). Col1(2.3)-tTA/TetO-Rs1 double transgenic (DT) mice, which showed osteoblast-specific constitutive G(s) signaling activity by the Rs1 receptor, were created. Femora and calvariae of DT and wild-type (WT) mice (6 and 15 weeks old) were analyzed by FTIR spectroscopy. WT and DT femora (3 and 9 weeks old) were imaged by SRµCT. Mineral-to-matrix ratio was 25% lower (P = 0.010), carbonate-to-phosphate ratio was 20% higher (P = 0.025), crystallinity was 4% lower (P = 0.004), and cross-link ratio was 11% lower (P = 0.025) in 6-week DT bone. Differences persisted in 15-week animals. Quantitative SRµCT analysis revealed substantial differences in mean values and heterogeneity of tissue mineral density (TMD). TMD values were 1,156 ± 100 and 711 ± 251 mg/cm(3) (mean ± SD) in WT and DT femoral diaphyses, respectively, at 3 weeks. Similar differences were found in 9-week animals. These results demonstrate that continuous G(s) activation in murine osteoblasts leads to deposition of immature bone tissue with reduced mineralization. Our findings suggest that bone tissue quality may be an important contributor to increased fracture risk in fibrous dysplasia patients.

Water-assisted CO(2) laser ablated glass and modified thermal bonding for capillary-driven bio-fluidic application.

The glass-based microfluidic chip has widely been applied to the lab-on-a-chip for clotting tests. Here, we have demonstrated a capillary driven flow chip using the water-assisted CO(2) laser ablation for crackless fluidic channels and holes as well as the modified low-temperature glass bonding with assistance of adhesive polymer film at 300 degrees Celsius. Effect of water depth on the laser ablation of glass quality was investigated. The surface hydrophilic property of glass and polymer film was measured by static contact angle method for hydrophilicity examination in comparison with the conventional polydimethylsiloxane (PDMS) material. Both low-viscosity deionized water and high-viscosity whole blood were used for testing the capillary-driving flow behavior. The preliminary coagulation testing in the Y-channel chip was also performed using whole blood and CaCl(2) solution. The water-assisted CO(2) laser processing can cool down glass during ablation for less temperature gradient to eliminate the crack. The modified glass bonding can simplify the conventional complex fabrication procedure of glass chips, such as high-temperature bonding, long consuming time and high cost. Moreover, the developed fluidic glass chip has the merit of hydrophilic behavior conquering the problem of traditional hydrophobic recovery of polymer fluidic chips and shows the ability to drive high-viscosity bio-fluids.

Utility of fiberoptic bronchoscopy before bronchial artery embolization for massive hemoptysis.

OBJECTIVE: We wanted to investigate the utility of performing fiberoptic bronchoscopy before bronchial artery embolization in patients with massive hemoptysis. MATERIALS AND METHODS: We retrospectively reviewed the cases of all patients with hemoptysis who had presented at either of two local hospitals, one county hospital and one community hospital, between 1988 and 2000 and who had undergone fiberoptic bronchoscopy before bronchial arteriography. All data were abstracted using a standardized coding form, and radiographs were independently reviewed by two of the authors. RESULTS: Twenty-nine patients meeting the inclusion criteria were identified; one patient was excluded because of missing radiographs. The remaining 28 patients consisted of 19 men and nine women, with an average age of 54.6 years (age range, 16-91 years). The clinically determined diagnoses of their symptoms were tuberculous bronchiectasis (n = 14; 50.0%); bronchogenic carcinoma (n = 4; 14.3%); active tuberculosis (n = 2; 7.1%); nontuberculous bronchiectasis (n = 2; 7.1%); active coccidioidomycosis, pancreaticobronchial fistula, arteriovenous malformation, and tetralogy of fallot (n =1 each; 3.6% each); and unknown cause (n = 2; 7.1%). The bleeding site determined through bronchoscopy was consistent with that determined through radiographs in 23 patients (82.1%); all had either unilateral disease (n = 15), bilateral disease with unilateral cavities (n = 5), or a preponderance of disease on one side (n = 3). Bronchoscopy was an essential tool in determining the bleeding site in only three patients (10.7%), all of whom had bronchiectasis without localizing features visible on chest radiographs. In the remaining two patients (7.1%), bronchoscopic findings were indeterminate, but radiographs were helpful. CONCLUSION: Fiberoptic bronchoscopy before bronchial artery embolization is unnecessary in patients with hemoptysis of known causation if the site of bleeding can be determined from radiographs and no bronchoscopic airways management is needed.

Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiple models of liver and bile duct injury suggests a role in tissue regeneration.

IFN-inducible protein-10 (IP-10/CXCL10) is a CXC chemokine that targets both T cells and NK cells. Elevation of IP-10 expression has been demonstrated in a number of human diseases, including chronic cirrhosis and biliary atresia. Cytokine-responsive gene-2 (Crg-2), the murine ortholog of IP-10, was induced following CCl(4) treatment of the hepatocyte-like cell line AML-12. Crg-2 expression was noted in vivo in multiple models of hepatic and bile duct injury, including bile duct ligation and CCl(4), D-galactosamine, and methylene dianiline toxic liver injuries. Induction of Crg-2 was also examined following two-thirds hepatectomy, a model that minimally injures the remaining liver, but that requires a large hepatic regenerative response. Crg-2 was induced in a biphasic fashion after two-thirds hepatectomy, preceding each known peak of hepatocyte DNA synthesis. Induction of Crg-2 was also observed in the kidney, gut, thymus, and spleen within 1 h of two-thirds hepatectomy. Characteristic of an immediate early gene, pretreatment of mice with the protein synthesis inhibitor cycloheximide before either two-thirds hepatectomy or CCl(4) injection led to Crg-2 superinduction. rIP-10 was demonstrated to have hepatocyte growth factor-inducing activity in vitro, but alone had no direct mitogenic effect on hepatocytes. Our data demonstrate that induction of Crg-2 occurs in several distinct models of liver injury and regeneration, and suggest a role for CRG-2/IP-10 in these processes.

Elderly subjects' ability to recover balance with a single backward step associates with body configuration at step contact.

BACKGROUND: In the event of a slip or trip, one's ability to recover a stable upright stance by stepping should depend on (a) the configuration of the body at the instant of step contact and (b) the forces generated between the foot and ground during step contact. In this study, we tested whether these two variables associate with elderly subjects' ability to recover balance by taking a single backward step after sudden release from an inclined position. METHODS: Twenty-six community-dwelling subjects (12 women, 14 men) of mean age 75+/-4 (SD) years each underwent five trials in which they were suddenly released from a backward inclination of 7 degrees and instructed to "recover balance with a single step." Body segment motions and foot contact forces were analyzed to determine step contact times, stepping angles, body lean angles at step contact, and the magnitudes and times (after step contact) of peak foot-floor contact forces and peak sagittal-plane torques at the ankle, knee, and hip of the stepping leg. RESULTS: Fifty percent of subjects were predominantly single steppers (successful at recovering with a single step in greater than three of five trials), 27% were multiple steppers (successful in less than two of five trials), and 23% were mixed response steppers (successful in two of five or three of five trials). Recovery style associated with the ratio of stepping angle divided by body lean angle at step contact (p = .003), which averaged 1.4+/-0.5 for single steppers and 0.6+/-0.5 for multiple steppers, but not with step contact time, stepping angle, or contact forces and joint torques during step contact. CONCLUSIONS: These results suggest that elderly subjects' ability to recover balance with a single backward step depends primarily on the configuration of the body (in particular, the ratio of stepping angle to body lean angle) at step contact.

Prevention of falls and fall-related fractures through biomechanics.

Falls and fall-related injuries are a major health problem for elderly people. Biomechanical studies provide important insight into the cause of such events and reveal new techniques for preventing them. The topics reviewed in this article include balance recovery, safe landing responses, impact forces during falls, and fracture prevention through exercise programs, hip pads, and energy-absorbing floors.

Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury.

We have identified a new murine transforming growth factor beta superfamily member, growth-differentiation factor 15 (Gdf15), that is expressed at highest levels in adult liver. As determined by Northern analysis, the expression of Gdf15 in liver was rapidly and dramatically up-regulated following various surgical and chemical treatments that cause acute liver injury and regeneration. In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA localization that appeared to reflect the known patterns of hepatocyte injury in each experimental treatment. In addition, treatment of two hepatocyte-like cell lines with either carbon tetrachloride or heat shock induced Gdf15 mRNA expression, indicating that direct cellular injury can induce Gdf15 expression in the absence of other cell types, such as inflammatory cells. In order to investigate the potential functions of Gdf15, we created Gdf15 null mice by gene targeting. Homozygous null mice were viable and fertile. Despite the dramatic regulation of Gdf15 expression observed in the partial-hepatectomy and carbon tetrachloride injury models, we found no differences in the injury responses between homozygous null mutants and wild-type mice. Our findings suggest either that Gdf15 does not have a regulatory role in liver injury and regeneration or that Gdf15 function within the liver is redundant with that of other signaling molecules.

Isolation, characterization and sequence analysis of five IgG monoclonal anti-beta 2-glycoprotein-1 and anti-prothrombin antigen-binding fragments generated by phage display.

We have isolated five monoclonal IgG anti-beta 2-glycoprotein-1 (anti-beta 2G-1) and anti-prothrombin Fab from a patient with autoantibodies to oxidized low-density lipoproteins by phage display method. Analysis of their binding specificity revealed that all three beta 2GP-1-enriched mAbs (B14, B22, B27) reacted with beta 2GP-1 while both prothrombin-isolated mAbs (P11 and P13) reacted with prothrombin. Intriguingly, mAb P11 reacted with beta 2GP-1 and prothrombin and showed comparable binding affinity to both Ags, with Kd values of 1.6 x 10-6 M for beta 2GP-1 vs 3.2 x 10-6 M for prothrombin. This clone may thus, define a hitherto unknown shared epitope between beta 2GP-1 and prothrombin. Sequence analysis of all five clones showed significant mutations of the expressed genes. One rearranged V-D-J segment was repeatedly employed by three clones (mAbs B22, B27, and P13). However, all three clones used different L chains. Of note, the pairing of VH6-D-J with the L5-Vk1 L chain in mAb P13 resulted in the loss of binding to beta 2GP-1 and specific reactivity to prothrombin. Together, these data suggest that while the VH6-D-J chain may be important in the binding to beta 2GP-1, pairing with certain L chains may influence this binding. These data are the first human IgG anti-beta 2GP-1 and anti-prothrombin sequences reported; both represent the major subsets of antiphospholipid Abs present in antiphospholipid syndrome patients.

Biomechanical influences on balance recovery by stepping.

Stepping represents a common means for balance recovery after a perturbation to upright posture. Yet little is known regarding the biomechanical factors which determine whether a step succeeds in preventing a fall. In the present study, we developed a simple pendulum-spring model of balance recovery by stepping, and used this to assess how step length and step contact time influence the effort (leg contact force) and feasibility of balance recovery by stepping. We then compared model predictions of step characteristics which minimize leg contact force to experimentally observed values over a range of perturbation strengths. At all perturbation levels, experimentally observed step execution times were higher than optimal, and step lengths were smaller than optimal. However, the predicted increase in leg contact force associated with these deviations was substantial only for large perturbations. Furthermore, increases in the strength of the perturbation caused subjects to take larger, quicker steps, which reduced their predicted leg contact force. We interpret these data to reflect young subjects' desire to minimize recovery effort, subject to neuromuscular constraints on step execution time and step length. Finally, our model predicts that successful balance recovery by stepping is governed by a coupling between step length, step execution time, and leg strength, so that the feasibility of balance recovery decreases unless declines in one capacity are offset by enhancements in the others. This suggests that one's risk for falls may be affected more by small but diffuse neuromuscular impairments than by larger impairment in a single motor capacity.

Common protective movements govern unexpected falls from standing height.

Simple energy considerations suggest that any fall from standing height has the potential to cause hip fracture. However, only 1-2% of falls among the elderly actually result in hip fracture, and less than 10% cause serious injury. This suggests that highly effective movement strategies exist for preventing injury during a fall. To determine the nature of these, we measured body segment movements as subjects (aged 22-35 yr) stood upon a gymnasium mattress and attempted to prevent themselves from falling after the mattress was made to translate abruptly. Subjects were more than twice as likely to fall after anterior translations of the feet, when compared to posterior or lateral translations. In falls which resulted in impact to the pelvis, a complex sequence of upper extremity movements allowed subjects to impact their wrist at nearly the same instant as the pelvis (average time interval between contacts = 38 ms), suggesting a sharing of contact energy between the two body parts. Finally, marked trunk rotation was exhibited in falls due to lateral (but not anterior or posterior) perturbations, resulting in the avoidance of impact to the lateral aspect of the hip. These results suggest that body segment movements during falls, rather than being random and unpredictable, involve a repeatable series of responses which facilitate safe landing.