Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is ...growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka-Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost-turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. SIGNIFICANCE: Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.
.
To colonise their host, pathogens must counter local environmental and immunological challenges. Here, we reveal that the fungal pathogen Candida albicans exploits diverse host-associated signals to ...promote immune evasion by masking of a major pathogen-associated molecular pattern (PAMP), β-glucan. Certain nutrients, stresses and antifungal drugs trigger β-glucan masking, whereas other inputs, such as nitrogen sources and quorum sensing molecules, exert limited effects on this PAMP. In particular, iron limitation triggers substantial changes in the cell wall that reduce β-glucan exposure. This correlates with reduced phagocytosis by macrophages and attenuated cytokine responses by peripheral blood mononuclear cells. Iron limitation-induced β-glucan masking depends on parallel signalling via the iron transceptor Ftr1 and the iron-responsive transcription factor Sef1, and the protein kinase A pathway. Our data reveal that C. albicans exploits a diverse range of specific host signals to trigger protective anticipatory responses against impending phagocytic attack and promote host colonisation.
The most common pathology in frontotemporal dementia (FTD) is tau-negative, ubiquitin-immunoreactive (ub-ir) neuronal inclusions (FTLD-U). Recently, we identified mutations in the progranulin (PGRN) ...gene as the cause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in 13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistent feature was the presence of ub-ir lentiform neuronal intranuclear inclusions (NII) in the neocortex and striatum. In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerative changes, ub-ir neurites and well-defined ub-ir neuronal cytoplasmic inclusions (NCI). In the striatum, there were numerous ub-ir neurites. NCI in the hippocampus usually had a granular appearance. In contrast, familial FTLD-U cases without PGRN mutations had no NII, less severe neocortical and striatal pathology and hippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also had NII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NII showed the same pattern of pathology as those with mutations. These findings suggest that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.
Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in ...reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.
By analogy with Pavlov’s dogs, certain pathogens have evolved anticipatory behaviours that exploit specific signals in the human host to prepare themselves against imminent host challenges. This ...adaptive prediction, a type of history-dependent microbial behaviour, represents a primitive form of microbial memory. For fungal pathogens, adaptive prediction helps them circumvent nutritional immunity, protects them against phagocytic killing, and activates immune evasion strategies. We describe how these anticipatory responses, and the contrasting lifestyles and evolutionary trajectories of fungal pathogens, have influenced the evolution of such adaptive behaviours, and how these behaviours affect host colonisation and infection.
Recent evidence indicates that fungal pathogens have evolved anticipatory behaviours.
These anticipatory behaviours exploit specific signals in the human host to prepare the fungus for imminent host challenges.
These anticipatory behaviours represent a primitive form of fungal memory.
These anticipatory behaviours can activate micronutrient acquisition mechanisms before a fungal pathogen is exposed to nutritional immunity. Masking of pathogen-associated molecular patterns at the fungal cell surface can attenuate subsequent immune recognition. Stress responses can be induced to protect the fungus against impending phagocytic killing mechanisms.
Together, these anticipatory behaviours promote immune evasion, fungal colonisation, and infection.
Formaldehyde (CH2O) is the most abundant aldehyde in the atmosphere, and it strongly affects photochemistry through its photolysis. We describe simultaneous measurements of CH2O and nitrogen dioxide ...(NO2) using broadband cavity-enhanced absorption spectroscopy in the ultraviolet spectral region. The light source consists of a continuous-wave diode laser focused into a Xenon bulb to produce a plasma that emits high-intensity, broadband light. The plasma discharge is optically filtered and coupled into a 1 m optical cavity. The reflectivity of the cavity mirrors is 0.99930 ± 0.00003 (1− reflectivity = 700 ppm loss) at 338 nm, as determined from the known Rayleigh scattering of He and zero air. This mirror reflectivity corresponds to an effective path length of 1.43 km within the 1 m cell. We measure the cavity output over the 315–350 nm spectral region using a grating monochromator and charge-coupled device array detector. We use published reference spectra with spectral fitting software to simultaneously retrieve CH2O and NO2 concentrations. Independent measurements of NO2 standard additions by broadband cavity-enhanced absorption spectroscopy and cavity ring-down spectroscopy agree within 2 % (slope for linear fit = 1.02 ± 0.03 with r2 = 0.998). Standard additions of CH2O measured by broadband cavity-enhanced absorption spectroscopy and calculated based on flow dilution are also well correlated, with r2 = 0.9998. During constant mixed additions of NO2 and CH2O, the 30 s measurement precisions (1σ) of the current configuration were 140 and 210 pptv, respectively. The current 1 min detection limit for extinction measurements at 315–350 nm provides sufficient sensitivity for measurement of trace gases in laboratory experiments and ground-based field experiments. Additionally, the instrument provides highly accurate, spectroscopically based trace gas detection that may complement higher precision techniques based on non-absolute detection methods. In addition to trace gases, this approach will be appropriate for measurements of aerosol extinction in ambient air, and this spectral region is important for characterizing the strong ultraviolet absorption by brown carbon aerosol.
We decompose the neutrinoless double-β decay matrix elements into sums of products over the intermediate nucleus with two less nucleons. We find that the sum is dominated by the J(π)=0(+) ground ...state of this intermediate nucleus for both the light and heavy neutrino decay processes. This provides a new theoretical tool for comparing and improving nuclear structure models. It also provides the connection to two-nucleon transfer experiments.
To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS).
This multicenter, randomized, double-blind, placebo-controlled, ...parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk.
Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose.
This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.
We present an analysis of Parker Solar Probe (PSP) IS IS observations of ∼30-300 keV n−1 ions on 2018 November 11 when PSP was about 0.25 au from the Sun. Five hours before the onset of a solar ...energetic particle (SEP) event, a coronal mass ejection (CME) was observed by STEREO-A/COR2, which crossed PSP about a day later. No shock was observed locally at PSP, but the CME may have driven a weak shock earlier. The SEP event was dispersive, with higher energy ions arriving before the lower energy ones. Timing suggests the particles originated at the CME when it was at ∼7.4R . SEP intensities increased gradually from their onset over a few hours, reaching a peak, and then decreased gradually before the CME arrived at PSP. The event was weak, having a very soft energy spectrum (−4 to −5 spectral index). The earliest arriving particles were anisotropic, moving outward from the Sun, but later, the distribution was observed to be more isotropic. We present numerical solutions of the Parker transport equation for the transport of 30-300 keV n−1 ions assuming a source comoving with the CME. Our model agrees well with the observations. The SEP event is consistent with ion acceleration at a weak shock driven briefly by the CME close to the Sun, which later dissipated before arriving at PSP, followed by the transport of ions in the interplanetary magnetic field.
PDF
