Engineering cancer selective virotherapies: are the pieces of the puzzle falling into place?

Advances in gene therapy, synthetic biology, cancer genomics and patient-derived cancer models have expanded the repertoire of strategies for targeting human cancers using viral vectors. Novel capsids, synthetic promoters and therapeutic payloads, are being developed and assessed via approaches such as rational design, pooled library screening and directed evolution. Ultimately, the goal is to generate precision-engineered viruses that target different facets of tumour cell biology, without compromising normal tissue and organ function. Here, we briefly review the opportunities for engineering cancer selectivity into viral vectors at both the cell extrinsic and intrinsic level. Such stringently tumour-targeted vectors can subsequently act as platforms for the delivery of potent therapeutic transgenes, including the exciting prospect of immunotherapeutic payloads. These have the potential to eradicate non-transduced cells through stimulation of systemic anti-cancer immune responses, thereby side-stepping the inherent challenge of achieving gene delivery to the entire cancer cell population. We discuss the importance of using advanced primary human cellular models, such as patient-derived cultures and organoids, to enable rapid screening and triage of novel candidates using disease-relevant human cellular models. We believe this combination of improved delivery and selectivity, through novel capsids and promoters, coupled with more potent choices for the combinations of immunotherapy-based payloads seems capable of finally delivering innovative new gene therapies for oncology. Many pieces of the puzzle of how to build a virus capable of targeting human cancers appear to be falling into place

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1-blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1-blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1-blockade to treat AD. However, confirmatory studies are required

Retrieval of atmospheric attenuation using combined ground-based and airborne 95-GHz cloud radar measurements

Includes bibliographical references (page 1353).Cloud measurements at millimeter-wave frequencies are affected by attenuation due to atmospheric gases, clouds, and precipitation. Estimation of the true equivalent radar reflectivity, Ze, is complicated because extinction mechanisms are not well characterized at these short wavelengths. This paper discusses cloud radar calibration and intercomparison of airborne and ground-based radar measurements and presents a unique algorithm for attenuation retrieval. This algorithm is based on dual 95-GHz radar measurements of the same cloud and precipitation volumes collected from opposing viewing angles. True radar reflectivity is retrieved by combining upward-looking and downward-looking radar profiles. This method reduces the uncertainty in radar reflectivity and attenuation estimates, since it does not require a priori knowledge of hydrometeors' microphysical properties. Results from this technique are compared with results retrieved from the Hitschfeld and Bordan algorithm, which uses single-radar measurements with path-integrated attenuation as a constraint. Further analysis is planned to employ this dual-radar algorithm in order to refine single-radar attenuation retrieval techniques, which will be used by operational sensors such as the CloudSat radar

Association of the 5-HTT Gene-Linked Promoter Region (5-HTTLPR) Polymorphism with Psychiatric Disorders: Review of Psychopathology and Pharmacotherapy

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication

The Effect of Exercise Training Modality on Serum Brain Derived Neurotrophic Factor Levels in Individuals with Type 2 Diabetes

Introduction: Brain derived neurotrophic factor (BDNF) has been implicated in memory, learning, and neurodegenerative disease. However, the relationship of BDNF with cardiometabolic risk factors is unclear, and the effect of exercise training on BDNF has not been previously explored in individuals with type 2 diabetes. Methods: Men and women (N=150) with type 2 diabetes were randomized to an aerobic exercise (aerobic), resistance exercise (resistance), or a combination of both (combination) for 9 months. Serum BDNF levels were evaluated at baseline and follow-up from archived blood samples. Results: Baseline serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures (all, p\u3e0.05). Similarly, no significant change in serum BDNF levels was observed following exercise training in the aerobic (-1649.4 pg/ml, CI: -4768.9 to 1470.2), resistance (-2351.2 pg/ml, CI: -5290.7 to 588.3), or combination groups (-827.4 pg/ml, CI: -3533.3 to 1878.5) compared to the control group (-2320.0 pg/ml, CI: -5750.8 to 1110.8). However, reductions in waist circumference were directly associated with changes in serum BDNF following training (r=0.25, p=0.005). Conclusions: Serum BDF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures at baseline. Likewise, serum BDNF measures were not altered by 9 months of aerobic, resistance, or combination training. However, reductions in waist circumference were associated with decreased serum BDNF levels. Future studies should investigate the relevance of BDNF with measures of cognitive function specifically in individuals with type-2 diabetes

Discovery of Two Nearby, Peculiar L Dwarfs from the 2MASS Proper Motion Survey: Young or Metal-Rich?

We present the discovery of two nearby L dwarfs from our 2MASS proper motion search, which uses multi-epoch 2MASS observations covering ~4700 square degrees of sky. 2MASS J18212815+1414010 and 2MASS J21481628+4003593 were overlooked by earlier surveys due to their faint optical magnitudes and their proximity to the Galactic Plane (10 degrees < |b| < 15 degrees). Assuming that both dwarfs are single, we derive spectrophotometric distances of ~10 pc, thus increasing the number of known L dwarfs within 10 pc to 10. In the near-infrared, 2MASS J21481628+4003593 shows a triangular-shaped H-band spectrum, strong CO absorption, and a markedly red J-Ks color (2.38+/-0.06) for its L6 optical spectral type. 2MASS J18212815+1414010 also shows a triangular-shaped H-band spectrum and a slightly red J-Ks color (1.78+/-0.05) for its L4.5 optical spectral type. Both objects show strong silicate absorption at 9-11 microns. Cumulatively, these features imply an unusually dusty photosphere for both of these objects. We examine several scenarios to explain the underlying cause for their enhanced dust content and find that a metal-rich atmosphere or a low-surface gravity are consistent with these results. 2MASS J18212815+1414010 may be young (and therefore have a low-surface gravity) based on its low tangential velocity of 10 km/s. On the other hand, 2MASS J21481628+4003593 has a high tangential velocity of 62 km/s and is therefore likely old. Hence, high metallicity and low-surface gravity may lead to similar effects.Comment: 9 pages, 4 tables, 13 figures. Accepted to Ap

First radial velocity results from the MINiature Exoplanet Radial Velocity Array (MINERVA)

The MINiature Exoplanet Radial Velocity Array (MINERVA) is a dedicated observatory of four 0.7m robotic telescopes fiber-fed to a KiwiSpec spectrograph. The MINERVA mission is to discover super-Earths in the habitable zones of nearby stars. This can be accomplished with MINERVA's unique combination of high precision and high cadence over long time periods. In this work, we detail changes to the MINERVA facility that have occurred since our previous paper. We then describe MINERVA's robotic control software, the process by which we perform 1D spectral extraction, and our forward modeling Doppler pipeline. In the process of improving our forward modeling procedure, we found that our spectrograph's intrinsic instrumental profile is stable for at least nine months. Because of that, we characterized our instrumental profile with a time-independent, cubic spline function based on the profile in the cross dispersion direction, with which we achieved a radial velocity precision similar to using a conventional "sum-of-Gaussians" instrumental profile: 1.8 m s$^{-1}$ over 1.5 months on the RV standard star HD 122064. Therefore, we conclude that the instrumental profile need not be perfectly accurate as long as it is stable. In addition, we observed 51 Peg and our results are consistent with the literature, confirming our spectrograph and Doppler pipeline are producing accurate and precise radial velocities.Comment: 22 pages, 9 figures, submitted to PASP, Peer-Reviewed and Accepte

(R)-Desmolactone Is a Sex Pheromone or Sex Attractant for the Endangered Valley Elderberry Longhorn Beetle Desmocerus californicus dimorphus and Several Congeners (Cerambycidae: Lepturinae)

We report here that (4R,9Z)-hexadec-9-en-4-olide [(R)-desmolactone] is a sex attractant or sex pheromone for multiple species and subspecies in the cerambycid genus Desmocerus. This compound was previously identified as a female-produced sex attractant pheromone of Desmocerus californicus californicus. Headspace volatiles from female Desmocerus aureipennis aureipennis contained (R)-desmolactone, and the antennae of adult males of two species responded strongly to synthetic (R)-desmolactone in coupled gas chromatography-electroantennogram analyses. In field bioassays in California, Oregon, and British Columbia, traps baited with synthetic (R)-desmolactone captured males of several Desmocerus species and subspecies. Only male beetles were captured, indicating that this compound acts as a sex-specific attractant, rather than as a signal for aggregation. In targeted field bioassays, males of the US federally threatened subspecies Desmocerus californicus dimorphus responded to the synthetic attractant in a dose dependent manner. Our results represent the first example of a ‘‘generic’’ sex pheromone used by multiple species in the subfamily Lepturinae, and demonstrate that pheromone-baited traps may be a sensitive and efficient method of monitoring the threatened species Desmocerus californicus dimorphus, commonly known as the valley elderberry longhorn beetle

Association between Changes in Muscle Quality with Exercise Training and Changes in Cardiorespiratory Fitness Measures in Individuals with Type 2 Diabetes Mellitus: Results from the HART-D Study

Introduction: Type 2 diabetes mellitus (T2DM) is associated with a reduction in muscle quality. However, there is inadequate empirical evidence to determine whether changes in muscle quality following exercise are associated with improvement in cardiorespiratory fitness (CRF) in individuals with T2DM. The objective of this study was to investigate the association between change in muscle quality following a 9-month intervention of aerobic training (AT), resistance training (RT) or a combination of both (ATRT) and cardiorespiratory fitness (CRF) in individuals with T2DM. Material and Methods A total of 196 participants were randomly assigned to a control, AT, RT, or combined ATRT for a 9-months intervention. The exposure variable was change in muscle quality [(Post: leg muscle strength/leg muscle mass)-[(Pre: leg muscle strength/leg muscle mass)]. Dependent variables were change in CRF measures including absolute and relative VO2peak, and treadmill time to exhaustion (TTE) and estimated metabolic equivalent task (METs). Results Continuous change in muscle quality was independently associated with change in absolute (β = 0.015; p = 0.019) and relative (β = 0.200; p = 0.005) VO2peak, and TTE (β = 0.170; p = 0.043), but not with estimated METs (p > 0.05). A significant trend was observed across tertiles of change in muscle quality for changes in absolute (β = 0.050; p = 0.005) and relative (β = 0.624; p = 0.002) VO2peak following 9 months of exercise training. No such association was observed for change in TTE and estimated METs (p > 0.05). Discussion: The results from this ancillary study suggest that change in muscle quality following exercise training is associated with a greater improvement in CRF in individuals with T2DM. Given the effect RT has on increasing muscle quality, especially as part of a recommended training program (ATRT), individuals with T2DM should incorporate RT into their AT regimens to optimize CRF improvement