Building a translational cancer dependency map for The Cancer Genome Atlas.

Cancer dependency maps have accelerated the discovery of tumor vulnerabilities that can be exploited as drug targets when translatable to patients. The Cancer Genome Atlas (TCGA) is a compendium of 'maps' detailing the genetic, epigenetic and molecular changes that occur during the pathogenesis of cancer, yet it lacks a dependency map to translate gene essentiality in patient tumors. Here, we used machine learning to build translational dependency maps for patient tumors, which identified tumor vulnerabilities that predict drug responses and disease outcomes. A similar approach was used to map gene tolerability in healthy tissues to prioritize tumor vulnerabilities with the best therapeutic windows. A subset of patient-translatable synthetic lethalities were experimentally tested, including PAPSS1/PAPSS12 and CNOT7/CNOT78, which were validated in vitro and in vivo. Notably, PAPSS1 synthetic lethality was driven by collateral deletion of PAPSS2 with PTEN and was correlated with patient survival. Finally, the translational dependency map is provided as a web-based application for exploring tumor vulnerabilities.

Low-dose radiation decreases Lrrk2 levels in the striatum of large mammalian brains: New venues to treat Parkinson's disease?

INTRODUCTION: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.

Fatigue Test Method to Evaluate the 50 Year Durability of Venous Stents.

OBJECTIVE: Iliofemoral venous obstructive disease can result in significant, potentially debilitating symptoms that can negatively affect quality of life. Unlike arterial disease, patients with deep venous disease have a significantly lower median age, therefore the need for long term stent patency becomes a matter of decades rather than years. Furthermore, iliofemoral lesions frequently require stent placement across the inguinal ligament. Such stents are subject to dynamic stress from leg movement and associated concerns for device fatigue, resulting in stent fracture. The aim of this study was to describe an in vitro 50 year stent fatigue test method designed to assess durability against dynamic stress induced device fracture. METHODS: Through literature review, cadaver studies, and computer modelling, the most challenging loading was confirmed to be hip flexion across the inguinal ligament. This occurs when the patient adjusts between a seated and standing position. Sit to stand hip flexion at the inguinal ligament was effectively simulated on the bench in this in vitro experimental study. RESULTS: When tested under challenge parameters, hip flexion was reliably found to cause fractures in non-venous nitinol stents. However, a dedicated self expanding nitinol venous stent, engineered for improved durability, underwent up to 50 years of simulated loading on the bench with 15% (3/20) of stents experiencing fractures at 50 years, compared with fractures in 35% (14/40) of non-venous stents tested to 1.4 years; no statistical testing was performed as durations do not match and the objective was to demonstrate the test method). CONCLUSION: The presented fatigue test method is a suitable approach for evaluating the durability of stents intended for venous use. Venous stents demonstrated superior fatigue resistance compared with non-venous stents via in vitro hip flexion testing.

MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small-cell lung cancer.

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases.

BACKGROUND: Single session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2cm) to determine the safety of preoperative SRS at escalating doses. METHODS: Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy for >4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. RESULTS: A total of 35 patients/36 lesions were enrolled. For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4 cm arm at 21Gy. The maximum tolerated dose (MTD) of SRS for >2-3 cm was not reached; and was 18 Gy for both >3-4 cm arm and >4-6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. CONCLUSION: Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

Proteomic changes in the hippocampus of large mammals after total-body low dose radiation.

There is a growing interest in low dose radiation (LDR) to counteract neurodegeneration. However, LDR effects on normal brain have not been completely explored yet. Recent analyses showed that LDR exposure to normal brain tissue causes expression level changes of different proteins including neurodegeneration-associated proteins. We assessed the proteomic changes occurring in radiated vs. sham normal swine brains. Due to its involvement in various neurodegenerative processes, including those associated with cognitive changes after high dose radiation exposure, we focused on the hippocampus first. We observed significant proteomic changes in the hippocampus of radiated vs. sham swine after LDR (1.79Gy). Mass spectrometry results showed 190 up-regulated and 120 down-regulated proteins after LDR. Western blotting analyses confirmed increased levels of TPM1, TPM4, PCP4 and NPY (all proteins decreased in various neurodegenerative processes, with NPY and PCP4 known to be neuroprotective) in radiated vs. sham swine. These data support the use of LDR as a potential beneficial tool to interfere with neurodegenerative processes and perhaps other brain-related disorders, including behavioral disorders.

Identifying opportunities for high resolution pesticide usage data to improve the efficiency of endangered species pesticide risk assessment.

The US pesticide registration and review process requires regular re-assessment of the risk of pesticide use to species listed under the Endangered Species Act (ESA), yet current assessment methods are inefficient when applied to hundreds of pesticides potentially impacting multiple species across a continent. Thus, many pesticides remain on the market without complete review. We assessed the value of using high resolution pesticide usage data in the risk assessment process to rapidly improve process efficiency. By using data available only in California, we found that high resolution data increased the number of species deemed not likely to be adversely affected by pesticides from <5 % to nearly 50 %. Across the contiguous US, we predicted that 48 % of species would be deemed not likely to be adversely affected using high resolution data, compared to 20 % without. However, if such data were available in just 11 states, 68 % of the available gains in efficiency could be obtained. Overall, using existing high-resolution data in California and a focused collection of such information from 11 other states could reduce risk assessment burden across the contiguous U.S. by one-quarter.

Three-Year Outcomes of the Abre Venous Self-Expanding Stent System in Patients with Symptomatic Iliofemoral Venous Outflow Obstruction.

PURPOSE: To report 36-month outcomes and subgroup analysis of the ABRE study evaluating the safety and effectiveness of the Abre venous self-expanding stent system for the treatment of symptomatic iliofemoral venous outflow obstruction disease. METHODS: The ABRE study was a prospective, multicenter, nonrandomized study that enrolled and implanted Abre venous stents in 200 participants (mean age 51.5 years [SD ± 15.9], 66.5% women) with symptomatic iliofemoral venous outflow obstruction at 24 global sites. Outcomes assessed through 36 months included patency, major adverse events, stent migration, stent fracture, and quality-of-life changes. Adverse events and imaging studies were adjudicated by independent clinical events committee and core laboratories, respectively. RESULTS: Primary, primary-assisted, and secondary patency through 36 months by Kaplan-Meier estimates were 81.6%, 84.8%, and 86.3%, respectively. The cumulative incidence of major adverse events through 36 months was 10.2%, mainly driven by 12 thrombosis events. Subgroup analyses demonstrated a primary patency of 76.5% in the acute deep vein thrombosis group, 70.4% in the postthrombotic syndrome group, and 97.1% in the nonthrombotic iliac vein lesion group through 36 months. The overall mean lesion length was 112.4 mm (SD ± 66.1). There were no stent fractures or migrations in this study. Quality of life and venous functional assessments demonstrated significant improvements from baseline to 36 months across all patient subsets. CONCLUSIONS: Results from the ABRE study demonstrated sustained patency with a good safety profile after implantation of a dedicated venous stent in patients with symptomatic iliofemoral venous outflow obstruction disease.

Intravascular Ultrasound Use in Peripheral Arterial and Deep Venous Interventions: Multidisciplinary Expert Opinion From SCAI/AVF/AVLS/SIR/SVM/SVS.

Percutaneous revascularization is the primary strategy for treating lower extremity venous and arterial disease. Angiography is limited by its ability to accurately size vessels, precisely determine the degree of stenosis and length of lesions, characterize lesion morphology, or correctly diagnose postintervention complications. These limitations are overcome with use of intravascular ultrasound (IVUS). IVUS has demonstrated the ability to improve outcomes following percutaneous coronary intervention, and there is increasing evidence to support its benefits in the setting of peripheral vascular intervention. At this stage in its evolution, there remains a need to standardize the use and approach to peripheral vascular IVUS imaging. This manuscript represents considerations and consensus perspectives that emerged from a roundtable discussion including 15 physicians with expertise in interventional cardiology, interventional radiology, and vascular surgery, representing 6 cardiovascular specialty societies, held on February 3, 2023. The roundtable's aims were to assess the current state of lower extremity revascularization, identify knowledge gaps and need for evidence, and determine how IVUS can improve care and outcomes for patients with peripheral arterial and deep venous pathology.

Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study.

PURPOSE: Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). METHODS AND MATERIALS: Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. RESULTS: The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P = .004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n = 162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P = .003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. CONCLUSIONS: Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).

Proteomic Changes in the Hippocampus after Repeated Explosive-Driven Blasts.

Repeated blast-traumatic brain injury (blast-TBI) has been hypothesized to cause persistent and unusual neurological and psychiatric symptoms in service members returning from war zones. Blast-wave primary effects have been supposed to induce damage and molecular alterations in the brain. However, the mechanisms through which the primary effect of an explosive-driven blast wave generate brain lesions and induce brain consequences are incompletely known. Prior findings from rat brains exposed to two consecutive explosive-driven blasts showed molecular changes (hyperphosphorylated-Tau, AQP4, S100ß, PDGF, and DNA-polymerase-ß) that varied in magnitude and direction across different brain regions. We aimed to compare, in an unbiased manner, the proteomic profile in the hippocampus of double blast vs sham rats using mass spectrometry (MS). Data showed differences in up- and down-regulation for protein abundances in the hippocampus of double blast vs sham rats. Tandem mass tag (TMT)-MS results showed 136 up-regulated and 94 down-regulated proteins between the two groups (10.25345/C52B8VP0X). These TMT-MS findings revealed changes never described before in blast studies, such as increases in MAGI3, a scaffolding protein at cell-cell junctions, which were confirmed by Western blotting analyses. Due to the absence of behavioral and obvious histopathological changes as described in our previous publications, these proteomic data further support the existence of an asymptomatic blast-induced molecular altered status (ABIMAS) associated with specific protein changes in the hippocampus of rats repeatedly expsosed to blast waves generated by explosive-driven detonations.

Variations and inconsistencies in venous ablation coverage policies between single-state and multistate carriers in the United States.

BACKGROUND: Vein ablation is a common and effective treatment for patients with chronic venous insufficiency. The overuse of vein ablation despite the existence of evidence-based guidelines has resulted in insurance companies developing restrictive policies for coverage that create barriers to appropriate care. This study compares the insurance coverage by single-state carriers (SSCs) and multistate carriers (MSCs), highlighting the variations and inconsistencies in the various policies. METHODS: The American Venous Forum Venous Policy Navigator was reviewed for the various policies available in the United States. The policies were divided into SSCs and MSCs. The characteristics of the policies, including the anatomic and hemodynamic criteria for specific veins, duration of conservative treatment, disease severity, symptoms, and types of procedures covered, were compared between the two groups. SAS, version 9.4 (SAS Institute Inc) was used for statistical analysis. RESULTS: A total of 122 policies were analyzed and divided between SSCs (n = 85; 69.7%) and MSCs (n = 37; 30.3%). A significant variation was found in the size requirement for great saphenous vein ablation. Although 48% of the policies did not specify a size criterion, the remaining policies indicated a minimal size, ranging from 3 to 5.5 mm. However, no significant differences were found between SSCs and MSCs. Similar findings were encountered for the small and anterior accessory saphenous veins. MSCs were more likely to define a saphenous reflux time >500 ms compared with SSCs (81.1% vs 58.8%; P = .04). A significant difference was found between the SSCs and MSCs in the criteria for perforator ablation in terms of size and reflux time. MSCs were significantly more likely to provide coverage for mechanochemical ablation than were SSCs (24.3% vs 8.2%; P = .03). SSCs were more likely to require ≥12 weeks of compression stocking therapy than were MSCs (76.5% vs 48.7%; P = .01). No significant differences were found in the clinical indications between the two groups; however, MSCs were more likely to mention major hemorrhage than were SSCs. CONCLUSIONS: The results of this study highlight the variations in policies for venous ablation, in particular, the striking inconsistencies in size criteria. MSCs were more likely to cover mechanochemical ablation and require a shorter duration of conservative therapy before intervention compared with SSCs. Evidence-based guidance is needed to develop more coherent policies for venous ablation coverage.

Neutrophil to lymphocyte ratio (NTLR) predicts local control and overall survival after stereotactic body radiotherapy (SBRT) in metastatic sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.

Low-dose brain radiation: lowering hyperphosphorylated-tau without increasing DNA damage or oncogenic activation.

Brain radiation has been medically used to alter the metabolism of cancerous cells and induce their elimination. Rarely, though, brain radiation has been used to interfere with the pathomechanisms of non-cancerous brain disorders, especially neurodegenerative disorders. Data from low-dose radiation (LDR) on swine brains demonstrated reduced levels of phosphorylated-tau (CP13) and amyloid precursor protein (APP) in radiated (RAD) versus sham (SH) animals. Phosphorylated-tau and APP are involved in Alzheimer's disease (AD) pathogenesis. We determined if the expression levels of hyperphosphorylated-tau, 3R-tau, 4R-tau, synaptic, intraneuronal damage, and DNA damage/oncogenic activation markers were altered in RAD versus SH swine brains. Quantitative analyses demonstrated reduced levels of AT8 and 3R-tau in hippocampus (H) and striatum (Str), increased levels of synaptophysin and PSD-95 in frontal cortex (FCtx), and reduced levels of NF-L in cerebellum (CRB) of RAD versus SH swine. DNA damage and oncogene activation markers levels did not differ between RAD and SH animals, except for histone-H3 (increased in FCtx and CRB, decreased in Str), and p53 (reduced in FCtx, Str, H and CRB). These findings confirm the region-based effects of sLDR on proteins normally expressed in larger mammalian brains and support the potential applicability of LDR to beneficially interfere against neurodegenerative mechanisms.

Venous compression syndromes in females: A descriptive review.

Venous compression syndromes have been described, yet the role of sex is poorly understood. Although iliac vein compression has been discussed more often with the advent of newer technologies, research has fallen short on defining epidemiology, best practices for evaluation and treatment, and differences in responses to treatment between men and females. The authors report on iliac vein compression, nonthrombotic renal vein compression, and other venous compression syndromes in females. Literature searches of PubMed were performed using the following keywords: females/females and May Thurner, venous stenting, venous outcomes, deep venous disease, deep venous compression, venous stenting, renal vein compression, renal vein surgery/stent, popliteal vein entrapment, venous thoracic vein entrapment, and popliteal vein entrapment. The articles prompted the authors to research further as the referenced articles were reviewed. Sex representation has not been addressed adequately in the research of venous compression syndromes, making the discussion of best treatment options and long-term outcomes difficult. More specific understanding of epidemiology and response to interventions will only come from research that addresses these issues directly, understanding that some of these syndromes occur rarely.

Functional characterization of a single nucleotide polymorphism associated with Alzheimer's disease in a hiPSC-based neuron model.

Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.

4D Printable Salicylic Acid Photopolymers for Sustained Drug Releasing, Shape Memory, Soft Tissue Scaffolds.

3D printing of pharmaceuticals offers a unique opportunity for long-term, sustained drug release profiles for an array of treatment options. Unfortunately, this approach is often limited by physical compounding or processing limitations. Modification of the active drug into a prodrug compound allows for seamless incorporation with advanced manufacturing methods that open the door to production of complex tissue scaffold drug depots. Here we demonstrate this concept using salicylic acids with varied prodrug structures for control of physical and chemical properties. The role of different salicylic acid derivatives (salicylic acid, bromosalicylic allyl ester, iodosalicylic allyl ester) and linker species (allyl salicylate, allyl 2-(allyloxy)benzoate, allyl 2-(((allyloxy)carbonyl)oxy)benzoate) were investigated using thiol-ene cross-linking in digital light processing (DLP) 3D printing to produce porous prodrug tissue scaffolds containing more than 50% salicylic acid by mass. Salicylic acid photopolymer resins were all found to be highly reactive (solidification within 5 s of irradiation at λ = 405 nm), while the cross-linked solids display tunable thermomechanical behaviors with low glass transition temperatures (Tgs) and elastomeric behaviors, with the carbonate species displaying an elastic modulus matching that of adipose tissue (approximately 65 kPa). Drug release profiles were found to be zero order, sustained release based upon hydrolytic degradation of multilayered scaffolds incorporating fluorescent modeling compounds, with release rates tuned through selection of the linker species. Cytocompatibility in 2D and 3D was further demonstrated for all species compared to polycarbonate controls, as well as salicylic acid-containing composites (physical incorporation), over a 2-week period using murine fibroblasts. The use of drugs as the matrix material for solid prodrug tissue scaffolds opens the door to novel therapeutic strategies, longer sustained release profiles, and even reduced complications for advanced medicine.

Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats.

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats.