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Cannabis, or marijuana, comprises many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and antiinflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis, and 14 have legalized recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms, and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned, and systematic approach to cannabis. The results of our national survey, unfortunately, found little consensus among institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use., Competing Interests: L.J.B. has served on an advisory board for Veloxis Pharmaceuticals and currently serves on their Speaker’s Bureau. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The pharmacokinetic profiles of medications are altered in overweight and underweight patients, but few studies have described these differences in patients with body mass index extremes. As solid organ transplant programs expand their candidate selection criteria to accommodate a growing population of patients with weight extremes, it has become imperative to understand and evaluate the impact weight extremes have on the pharmacokinetics of life-sustaining immunosuppression in this population. This review will describe pharmacokinetic and dosing considerations for weight extremes in solid organ transplant recipients, including changes following bariatric surgeries, non-pharmacologic and pharmacologic management strategies for weight loss and gain, and potential drug-drug interactions with popular weight management products., (© 2021 Pharmacotherapy Publications, Inc.)

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

Background: Due to the lack of effective therapies and poor prognosis in TNBC (triple-negative breast cancer) patients, there is a strong need to develop effective novel targeted therapies for this subtype of breast cancer. Inhibition of heat shock protein 90 (HSP90), a conserved molecular chaperone that is involved in the regulation of oncogenic client proteins, has shown to be a promising therapeutic approach for TNBC. However, both intrinsic and acquired resistance to HSP90 inhibitors (HSP90i) limits their effectiveness in cancer patients., Methods: We developed models of acquired resistance to HSP90i by prolonged exposure of TNBC cells to HSP90i (ganetespib) in vitro. Whole transcriptome profiling and a 328-compound bioactive small molecule screen were performed on these cells to identify the molecular basis of acquired resistance to HSP90i and potential therapeutic approaches to overcome resistance., Results: Among a panel of seven TNBC cell lines, the most sensitive cell line (Hs578T) to HSP90i was selected as an in vitro model to investigate acquired resistance to HSP90i. Two independent HSP90i-resistant clones were successfully isolated which both showed absence of client proteins degradation, apoptosis induction and G2/M cell cycle arrest after treatment with HSP90i. Gene expression profiling and pathway enrichment analysis demonstrate significant activation of the survival JAK-STAT signalling pathway in both HSP90i-resistant clones, possibly through IL6 autocrine signalling. A bioactive small molecule screen also demonstrated that the HSP90i-resistant clones showed selective sensitivity to JAK2 inhibition. Inhibition of JAK and HSP90 caused higher induction of apoptosis, despite prior acquired resistance to HSP90i., Conclusions: Acquired resistance to HSP90i in TNBC cells is associated with an upregulated JAK-STAT signalling pathway. A combined inhibition of the JAK-STAT signalling pathway and HSP90 could overcome this resistance. The benefits of the combined therapy could be explored further for the development of effective targeted therapy in TNBC patients.

Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation therapy in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation therapy. In this study, we examined the normal tissue response in mice treated with PARP inhibitors (BMN673 or AZD2281) in combination with thoracic irradiation., Methods and Materials: The antitumor effects of fractionated irradiation (5 Gy × 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. The normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated irradiation, 5 Gy × 4, delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. The DNA damage response in the esophagus and skin was assessed by γH2AX immunohistochemistry., Results: While PARP inhibition enhanced irradiation-induced tumor growth inhibition in nude mice, it was also associated with significant body weight loss and increased damage to the esophagus and skin within the field of irradiation in C57BL6 mice. PARP inhibition compromised the repair of irradiation-induced DNA damage in the esophagus and skin., Conclusions: Although PARP inhibition enhanced the antitumor response to fractionated irradiation, it also enhanced the irradiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies using PARP inhibitors and radiation therapy, in particular where the field of irradiation includes the esophagus., (Copyright © 2017. Published by Elsevier Inc.)

Background: Until recently, transplantation from hepatitis C-positive donors was relatively contraindicated as eradication of active hepatitis C previously required an interferon-based regimen that has been associated with rejection in solid organ transplantation. New interferon-free treatment regimens for hepatitis C have fewer adverse events and higher cure rates than interferon-based regimens. Interferon-free regimens have been shown to be safe in the liver transplantation literature, but little is known about the safety and efficacy of treatment in heart transplantation., Case Description and Discussion: Here we report a case of successful eradication of hepatitis C with a non-interferon-based regimen using ledipasvir-sofosbuvir following combined orthotopic heart and liver transplantation. Based on the prevalence of hepatitis C in the general population, inclusion of hepatitis C-positive donors for heart transplantation can expand this component of the donor pool 3- to 6-fold., Conclusions: In carefully selected patients and recipients, inclusion of hepatitis C-positive donors may allow for expansion of the donor pool., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The adoption of electronic prescribing is on the rise, as it reduces medication errors compared to handwritten orders. The inadvertent dispensing of discontinued medications is a type of medication error that is less well described, but one that can lead to adverse events. Software for electronic prescriptions transmits orders for refills or new prescriptions, but not discontinuations, to the pharmacy. Medications that have been stopped are displayed only at the prescribing facility's electronic medical record (EMR). This report describes five cases in which the pharmacy dispensed electronically discontinued medications, two of which contributed to adverse outcomes.

The proper orthogonal decomposition method is applied to the analysis of particle image velocimetry data obtained for a supersonic rectangular jet operated at underexpanded conditions. Phase-locked velocity field data were used to calculate the eigenfunctions and the eigenvalues. It was found that a large fraction of the total energy is contained within the first two modes. The essential features of the jet are thus captured with only two functions. A low-dimensional model for the dynamical behavior is then constructed using Galerkin projection of the isentropic compressible Navier-Stokes equations. The reduced model compares reasonably well with the experimental findings.

We describe an on-line particle-image velocimeter (PIV) and its implementation for the measurement of the velocity field in steady and unsteady flows. The instrument uses up-to-date solid-state sensors, dedicated electronic boards, and digital microcomputers to combine the image-acquisition and processing steps into a single, fully integrated unit. A calibration experiment evaluates the accuracy of the velocity measurement instrument. The experiment consists of the measurement of the velocity distribution of a laminar wall jet and shows that the velocity, as well as the vorticity profiles, obtained by using the on-line PIV compare well with those obtained by means of a conventional photographic PIV and a numerical prediction.

An optical velocity bias device for use with the particle image velocimetry technique is implemented and successfully used to map a high-speed flow with velocity reversal and a large dynamic range.