Assessment of a SARS-CoV-2 wastewater monitoring program in El Paso, Texas, from November 2020 to June 2022.

The border city of El Paso, Texas, and its water utility, El Paso Water, initiated a SARS-CoV-2 wastewater monitoring program to assess virus trends and the appropriateness of a wastewater monitoring program for the community. Nearly weekly sample collection at four wastewater treatment facilities (WWTFs), serving distinct regions of the city, was analyzed for SARS-CoV-2 genes using the CDC 2019-Novel coronavirus Real-Time RT-PCR diagnostic panel. Virus concentrations ranged from 86.7 to 268,000 gc/L, varying across time and at each WWTF. The lag time between virus concentrations in wastewater and reported COVID-19 case rates (per 100,00 population) ranged from 4-24 days for the four WWTFs, with the strongest trend occurring from November 2021 - June 2022. This study is an assessment of the utility of a geographically refined SARS-CoV-2 wastewater monitoring program to supplement public health efforts that will manage the virus as it becomes endemic in El Paso.

A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes.

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. RESULTS: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. CONCLUSIONS: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

Impact of Frailty on Short-Term Outcomes After Laparoscopic and Open Hepatectomy.

BACKGROUND: Although laparoscopic hepatectomy (LH) is associated with improved short-term outcomes compared to open hepatectomy (OH), it is unknown whether frail patients also benefit from LH. The aim of this study was to evaluate the impact of frailty on post-operative outcomes after LH and OH. PATIENTS AND METHODS: Consecutive patients who underwent LH and OH between January 2011 and December 2018 were identified from a prospective database. Frailty was assessed using the modified Frailty Index (mFI), with patients scoring mFI ≥ 1 deemed to be frail. RESULTS: Of 1826 patients, 34.7% (N = 634) were frail and 18.6% (N = 340) were elderly (≥ 75 years). Frail patients had significantly higher 90-day mortality (6.6% vs. 2.9%, p < 0.001) and post-operative complications (36.3% vs. 26.1%, p < 0.001) than those who were not frail, effects that were independent of patient age on multivariate analysis. For those undergoing minor resections, the benefits of LH vs. OH were similar for frail and non-frail patients. Length of hospital stay was 53% longer in OH (vs. LH) in frail patients, compared to 58% longer in the subgroup of non-frail patients. CONCLUSIONS: Frailty is independently associated with inferior post-operative outcomes in patients undergoing hepatectomy. However, the benefits of laparoscopic (compared to open) hepatectomy are similar for frail and non-frail patients. Frailty should not be a contraindication to laparoscopic minor hepatectomy in carefully selected patients.

Tunable pH-Sensitive 2-Carboxybenzyl Phosphoramidate Cleavable Linkers.

We previously described a pH-sensitive phosphoramidate linker scaffold that can be tuned to release amine-containing drugs at various pH values. In these previous studies it was determined that the tunability of this linker was dependent upon the proximity of an acidic group (e.g., carboxylic acid or pyridinium). In this study, we confirmed that the tunability of pH-triggered amine-release was also dependent upon the pKa of the proximal acidic group. A series of 2-carboxybenzyl phosphoramidates was prepared in which the pKa of the proximal benzoic acid was predictably attenuated by substituents on the benzoate ring consistent with their σ-values.

Optimized Reconstruction Techniques for Multiplexed Dual-Gate Ion Mobility Mass Spectrometry Experiments.

When coupling drift-tube gas-phase ion mobility separations with ion trapping mass analyzers an integrative, stepped approach to spectral reconstruction is a logical, yet highly inefficient means to determine gas-phase mobility coefficients. This experimental mode is largely predicated on the respective time scales of the two techniques each requiring tens of milliseconds to complete under routine conditions. Multiplexing techniques, such as Fourier and Hadamard based techniques, are a potential solution but still require extended experimental times that are not fully compatible with modern front-end separation schemes. Using a basis pursuit denoising (BPDN) approach to deconvolute Fourier transform ion mobility mass spectrometry (FT-IMMS) drift time spectra, we demonstrate significant time savings while maintaining a high degree of spectral resolution and signal-to-noise ratio. Under ideal conditions, the FT-IMMS operates with increased ion transmission (up to 25%); however, the linear chirp that spans into the kHz range often leads to significant levels of ion gate depletion, which limit both resolving power and ion transmission. The method proposed in this manuscript demonstrates the potential to reduce IMS acquisition time while simultaneously maximizing spectral resolution at longer effective gate pulse widths compared to the traditional set of multiplexing and signal averaging experiments.

Small Molecule Antagonist of Cell Surface Glycosaminoglycans Restricts Mouse Embryonic Stem Cells in a Pluripotent State.

Recently, the field of stem cell-based regeneration has turned its attention toward chemical approaches for controlling the pluripotency and differentiation of embryonic stem cells (ESCs) using drug-like small molecule modulators. Growth factor receptors or their associated downstream kinases that regulate intracellular signaling pathways during differentiation are typically the targets for these molecules. The glycocalyx, which plays an essential role in actuating responses to growth factors at the cellular boundary, offers an underexplored opportunity for intervention using small molecules to influence differentiation. Here, we show that surfen, an antagonist of cell-surface glycosaminoglycans required for growth factor association with cognate receptors, acts as a potent and general inhibitor of differentiation and promoter of pluripotency in mouse ESCs. This finding shows that drugging the stem cell Glycome with small molecules to silence differentiation cues can provide a powerful new alternative to existing techniques for controlling stem cell fate. Stem Cells 2018;36:45-54.

Ambient Pressure Inverse Ion Mobility Spectrometry Coupled to Mass Spectrometry.

Although higher resolving powers are often achieved using ambient pressure drift tube ion mobility mass spectrometry (DT-IMMS) systems, lower duty cycles are often required which directly impacts sensitivity. Moreover, the mechanism of ion gating using Bradbury-Nielsen or Tyndall-Gate configurations routinely results in ion gate depletion effects which discriminate against low mobility ions. This paper reports a new method of ambient pressure ion mobility operation in which inverse ion mobility spectrometry is coupled to a time-of-flight mass spectrometer to improve sensitivity and minimize the effects of ion gate depletion. In this mode of operation, the duty cycle is improved to approximate 99% from a typical value of less than 1%, improving the signal intensity by over 2 orders of magnitude. Another advantage of inverse ion mobility mass spectrometry is a reduction of the impact of ion gate depletion on low mobility molecules that translates into higher sensitivity for this class of analytes. To demonstrate these benefits afforded by this instrumental mode of operation differences in sensitivity, resolving power, and ion discrimination are compared between the inverse and normal modes of operation using tetraalkylammonium standards. These results show that the ion throughput is significantly increased for analytes with a broad range of mobilities with little impact on resolving power. While the mobility-based discrimination is minimized using the inverse mode of operation, the noise level in the inverse mode is highly dependent upon the stability of ionization source.

Correlation ion mobility spectrometry.

Using a linearly swept chirp function to modulate a Bradbury-Nielsen (BN) ion gate and application of a common signal processing technique (cross-correlation), we outline a method for obtaining high resolution IMS-MS spectra with ion gate duty cycles approaching 50%. Correlation IMS (CIMS) offers advantages over current multiplexing approaches in IMS-MS, which include the Hadamard and Fourier transforms, by minimizing transform artifacts while maintaining high ion throughput. Although cross-correlation techniques have been utilized previously in the field of IMS, to the best of our knowledge, this approach has not been utilized to obtain spectrum that resembles traditional IMS spectrum with resolving powers approaching the theoretical limit. This new approach relies on a linear sweep, which is a swept frequency signal, commonly utilized in different applications because of its compatibility with the fast Fourier transform (FFT). However, unlike spectra derived from Fourier transformation, CIMS yields data sampling rates that are not dependent upon terminal frequency and takes advantage of several factors unique to IMS operation; the non-linear response of ions at relatively low gate pulse widths, fluctuations in intensity, and peak profiles resembling the input gate pulse vector observed especially noted at low gating frequencies.

Structure of the Bacillus anthracis Sortase A Enzyme Bound to Its Sorting Signal: A FLEXIBLE AMINO-TERMINAL APPENDAGE MODULATES SUBSTRATE ACCESS.

The endospore forming bacterium Bacillus anthracis causes lethal anthrax disease in humans and animals. The ability of this pathogen to replicate within macrophages is dependent upon the display of bacterial surface proteins attached to the cell wall by the B. anthracis Sortase A ((Ba)SrtA) enzyme. Previously, we discovered that the class A (Ba)SrtA sortase contains a unique N-terminal appendage that wraps around the body of the protein to contact the active site of the enzyme. To gain insight into its function, we determined the NMR structure of (Ba)SrtA bound to a LPXTG sorting signal analog. The structure, combined with dynamics, kinetics, and whole cell protein display data suggest that the N terminus modulates substrate access to the enzyme. We propose that it may increase the efficiency of protein display by reducing the unproductive hydrolytic cleavage of enzyme-protein covalent intermediates that form during the cell wall anchoring reaction. Notably, a key active site loop (ß7/ß8 loop) undergoes a disordered to ordered transition upon binding the sorting signal, potentially facilitating recognition of lipid II.

Tunable pH-Sensitive Linker for Controlled Release.

We have developed a novel pH-sensitive linker based on a phosphoramidate scaffold that can be tuned to release amine-containing drug molecules at various pH values. The pH-triggered phosphoramidate-based linkers are responsive to pH alone and do not require intracellular enzymatic action to initiate drug release. Key to the pH-triggered amine release from these linkers is a proximal acidic group (e.g., pyridinium or carboxylic acid) to promote the hydrolysis of the phosphoramidate P-N bond, presumably through an intramolecular general-acid type mechanism. Phosphoramidate hydrolysis is largely governed by the pKa of the leaving amine (e.g., primary, secondary, aniline). However, the proximity of the neighboring pyridine group attenuates the stability of the P-N bond to hydrolysis, thus allowing for control over the release of an amine from the phosphoramidate center. Based on the model scaffolds examined, phosphoramidate-based linkers could be selected for particular properties for controlled-release applications such as amine type, stability under physiological conditions, or release rates at various pH values such as intracellular endosomal conditions. The tunability of the phosphoramidate scaffold is expected to find broad applicability in various controlled drug-release applications such as antibody or small-molecule drug conjugates, drug-eluting stents, prodrug activation, as well as intracellular trafficking studies in which pH changes can trigger the release of turn-on dyes.

Second-Generation Tunable pH-Sensitive Phosphoramidate-Based Linkers for Controlled Release.

We developed a second generation of tunable pH-sensitive linkers based on our phosphoramidate scaffold to release amine-containing drugs under acidic conditions. The pH-triggered phosphoramidate-based linkers are responsive to pH and do not require intracellular enzymatic action to initiate drug release. On the basis of the model scaffolds examined, phosphoramidate-based linkers were selected for particular properties for controlled release applications such as amine type, stability under physiological conditions, or release rates at various pH values such as intracellular endosomal conditions. Key to the pH-triggered amine release from these linker is a proximal carboxylic acid to promote hydrolysis of the phosphoramidate P-N bond, presumably through an intramolecular general acid-type mechanism. Phosphoramidate hydrolysis is largely governed by the pKa of the leaving amine. However, the proximity of the neighboring carboxylic acid attenuates the stability of the P-N bond to hydrolysis, thus allowing for control over the release of an amine from the phosphoramidate center. In addition, we observed that the Thorpe-Ingold effect and rigidification of the scaffold could further enhance the rate of release. Esterification of the neighboring carboxylic acid was found to protect the scaffold from rapid release at low pH. This latter observation is particularly noteworthy as it suggests that the phosphoramidate-based drug-conjugate scaffold can be protected as an ester prodrug for oral administration. While the tunability phosphoramidate linkers is attractive for applications in intracellular trafficking studies in which pH changes can trigger release of turn-on dyes, antibody drug conjugates, small-molecule drug conjugates, and drug eluting stents (DES), the promise of oral delivery of drug conjugates is expected to have broad impact in controlled release applications.

A two-phase approach to Fourier transform ion mobility time-of-flight mass spectrometry.

It is well known that the duty cycle of common drift-tube ion mobility experiments is often below 1%. However, multiplexing approaches such as Fourier and Hadamard pulsing schemes have been shown to independently enhance the throughput of ion mobility spectrometry (IMS) experiments to levels that approach 50%. While challenges remain to their broad scale implementation we describe a new Fourier transform (FT) IMS experiment that is directly compatible with standard drift tube ion mobility mass spectrometers (DT-IMMS). Compared to previous FT-IMS experiments, our new approach requires only a single gate and circumvents the need for signal apodization by combining data from two frequency pulsing sequences 180° out of phase. Assessment of our initial results highlights an increase in signal-to-noise (SNR) relative to both previous implementations FT-IMS experiments and signal averaged (SA) experiments. For select tetraalkylammonium salts SNR improvements of more than one order of magnitude are routinely possible. To explore the performance metrics associated with the technique a number of experimental variables were systematically altered including frequency sweep range, sweep time, and data acquisition time. Using this experimental design we present the key aspects, considerations, and minimum resources necessary for other IMS researchers to incorporate this operational mode into their research. The two-phase FT-IMMS technique offers a tractable mechanism to enhance sensitivity for IMMS measurements and its broad-scale adoption by IMMS researchers promises to enhance the acquisition speed for mobility measurements using hybrid instrumentation.

The Physical Compatibility of Glycopyrrolate and Rocuronium.

OBJECTIVE: Scientific evidence has rarely, if at all, been reported in the literature demonstrating analytical confirmation of the physical compatibility and stability of glycopyrrolate and rocuronium combined. The purpose of this experiment was to determine if glycopyrrolate and rocuronium are physically compatible. METHODS: Glycopyrrolate and rocuronium were combined in various containers, observed over a 60-minute period, and compared against positive and negative controls. Measured metrics included color change, precipitate formation, Tyndall beam test, turbidity, and pH. Statistical analyses were used to assess significance of data trends. RESULTS: The combination of glycopyrrolate and rocuronium did not result in any color change, precipitate formation, a positive Tyndall beam test, or a significantly positive turbidity and did not result in any significant change in pH, regardless of container. CONCLUSION: Per the protocol used in this study, glycopyrrolate and rocuronium were determined to be physically compatible.

Morphine-induced osteolysis and hypersensitivity is mediated through toll-like receptor-4 in a murine model of metastatic breast cancer.

ABSTRACT: The propensity for breast cancer to metastasize to bone is coupled to the most common complaint among breast cancer patients: bone pain. Classically, this type of pain is treated using escalating doses of opioids, which lack long-term efficacy due to analgesic tolerance, opioid-induced hypersensitivity, and have recently been linked to enhanced bone loss. To date, the molecular mechanisms underlying these adverse effects have not been fully explored. Using an immunocompetent murine model of metastatic breast cancer, we demonstrated that sustained morphine infusion induced a significant increase in osteolysis and hypersensitivity within the ipsilateral femur through the activation of toll-like receptor-4 (TLR4). Pharmacological blockade with TAK242 (resatorvid) as well as the use of a TLR4 genetic knockout ameliorated the chronic morphine-induced osteolysis and hypersensitivity. Genetic MOR knockout did not mitigate chronic morphine hypersensitivity or bone loss. In vitro studies using RAW264.7 murine macrophages precursor cells demonstrated morphine-enhanced osteoclastogenesis that was inhibited by the TLR4 antagonist. Together, these data indicate that morphine induces osteolysis and hypersensitivity that are mediated, in part, through a TLR4 receptor mechanism.

Stem Cell Microarrays for Assessing Growth Factor Signaling in Engineered Glycan Microenvironments.

Extracellular glycans, such as glycosaminoglycans (GAGs), provide an essential regulatory component during the development and maintenance of tissues. GAGs, which harbor binding sites for a range of growth factors (GFs) and other morphogens, help establish gradients of these molecules in the extracellular matrix (ECM) and promote the formation of active signaling complexes when presented at the cell surface. As such, GAGs have been pursued as biologically active components for the development of biomaterials for cell-based regenerative therapies. However, their structural complexity and compositional heterogeneity make establishing structure-function relationships for this class of glycans difficult. Here, a stem cell array platform is described, in which chemically modified heparan sulfate (HS) GAG polysaccharides are conjugated to a gelatin matrix and introduced into a polyacrylamide hydrogel network. This array allowed for direct analysis of HS contributions to the signaling via the FGF2-dependent mitogen activated protein kinase (MAPK) pathway in mouse embryonic stem cells. With the recent emergence of powerful synthetic and recombinant technologies to produce well-defined GAG structures, a platform for analyzing both growth factor binding and signaling in response to the presence of these biomolecules will provide a powerful tool for integrating glycans into biomaterials to advance their biological properties and applications.

Cell surface photoengineering enables modeling of glycocalyx shedding dynamics.

The cellular glycocalyx, composed of membrane associated glycoproteins and glycolipids, is a complex and dynamic interface that facilitates interactions between cells and their environment. The glycocalyx composition is continuously changing through biosynthesis of new glycoconjugates and membrane turnover. Various glycocalyx components, such as mucins, can also be rapidly shed from the cell surface in response to acute events, such as pathogenic threat. Mucins, which are large extended glycoproteins, deliver important protective functions against infection by creating a physical barrier at the cell surface and by capturing and clearing pathogens through shedding. Evaluating these mucin functions may provide better understanding of early stages of pathogenesis; however, tools to tailor the composition and dynamics of the glycocalyx with precision are still limited. Here, we report a chemical cell surface engineering strategy to model the shedding behavior of mucins with spatial and temporal control. We generated synthetic mucin mimetic glycopolymers terminated with a photolabile membrane anchor, which could be introduced into the membranes of living cells and, subsequently, released upon exposure to UV light. By tuning the molecular density of the artificial glycocalyx we evaluated lectin crosslinking and its effect on shedding, showing that lectins can stabilize the glycocalyx and limit release of the mucin mimetics from the cell surface. Our findings indicate that endogenous and pathogen-associated lectins, which are known to interact with the host-cell glycocalyx, may alter mucin shedding dynamics and influence the protective properties of the mucosal barrier. More broadly, we present a method which enables photoengineering of the glycocalyx and can be used to facilitate the study of glycocalyx dynamics in other biological contexts.

Genomic and Functional Characterization of Vancomycin-Resistant Enterococci-Specific Bacteriophages in the Galleria mellonella Wax Moth Larvae Model.

Phages are naturally occurring viruses that selectively kill bacterial species without disturbing the individual's normal flora, averting the collateral damage of antimicrobial usage. The safety and the effectiveness of phages have been mainly confirmed in the food industry as well as in animal models. In this study, we report on the successful isolation of phages specific to Vancomycin-resistant Enterococci, including Enterococcus faecium (VREfm) and Enterococcus faecalis from sewage samples, and demonstrate their efficacy and safety for VREfm infection in the greater wax moth Galleria mellonella model. No virulence-associated genes, antibiotic resistance genes or integrases were detected in the phages' genomes, rendering them safe to be used in an in vivo model. Phages may be considered as potential agents for therapy for bacterial infections secondary to multidrug-resistant organisms such as VREfm.

Metabolic profiling reveals nutrient preferences during carbon utilization in Bacillus species.

The genus Bacillus includes species with diverse natural histories, including free-living nonpathogenic heterotrophs such as B. subtilis and host-dependent pathogens such as B. anthracis (the etiological agent of the disease anthrax) and B. cereus, a cause of food poisoning. Although highly similar genotypically, the ecological niches of these three species are mutually exclusive, which raises the untested hypothesis that their metabolism has speciated along a nutritional tract. Here, we developed a pipeline for quantitative total assessment of the use of diverse sources of carbon for general metabolism to better appreciate the "culinary preferences" of three distinct Bacillus species, as well as related Staphylococcus aureus. We show that each species has widely varying metabolic ability to utilize diverse sources of carbon that correlated to their ecological niches. This approach was applied to the growth and survival of B. anthracis in a blood-like environment and find metabolism shifts from sugar to amino acids as the preferred source of energy. Finally, various nutrients in broth and host-like environments are identified that may promote or interfere with bacterial metabolism during infection.

Antiviral Resistance and Phage Counter Adaptation to Antibiotic-Resistant Extraintestinal Pathogenic Escherichia coli.

Extraintestinal pathogenic Escherichia coli (ExPEC), often multidrug resistant (MDR), is a leading cause of urinary tract and systemic infections. The crisis of emergent MDR pathogens has led some to propose bacteriophages as a therapeutic. However, bacterial resistance to phage is a concerning issue that threatens to undermine phage therapy. Here, we demonstrate that E. coli sequence type 131, a circulating pandemic strain of ExPEC, rapidly develops resistance to a well-studied and therapeutically active phage (ϕHP3). Whole-genome sequencing of the resisters revealed truncations in genes involved in lipopolysaccharide (LPS) biosynthesis, the outer membrane transporter ompA, or both, implicating them as phage receptors. We found ExPEC resistance to phage is associated with a loss of fitness in host microenvironments and attenuation in a murine model of systemic infection. Furthermore, we constructed a novel phage-bacterium bioreactor to generate an evolved phage isolate with restored infectivity to all LPS-truncated ExPEC resisters. This study suggests that although the resistance of pandemic E. coli to phage is frequent, it is associated with attenuation of virulence and susceptibility to new phage variants that arise by directed evolution.IMPORTANCE In response to the rising crisis of antimicrobial resistance, bacteriophage (phage) therapy has gained traction. In the United States, there have been over 10 cases of largely successful compassionate-use phage therapy to date. The resilience of pathogens allowing their broad antibiotic resistance means we must also consider resistance to therapeutic phages. This work fills gaps in knowledge regarding development of phage resisters in a model of infection and finds critical fitness losses in those resisters. We also found that the phage was able to rapidly readapt to these resisters.

Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models.

Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced antinociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid antinociception in cancer-induced bone pain in female BALB/c mice and chemotherapy-induced peripheral neuropathy in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours, pain behaviors were evaluated after analgesic drug treatment. Heat shock protein 90 inhibition in the brain or systemically completely blocked morphine and oxymorphone antinociception in chemotherapy-induced peripheral neuropathy; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin antinociception. We also found that the Hsp90 isoform Hsp90α and the cochaperone Cdc37 were responsible for the observed changes in opioid antinociception. By contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid antinociception in cancer-induced bone pain. These results demonstrate that Hsp90 inhibitors block opioid antinociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.