Antimicrobial therapy during cancer treatment: Beyond antibacterial effects.

Cancer treatment options have evolved to include immunotherapy and targeted therapy, in addition to traditional chemoradiation. Chemoradiation places the patient at a higher risk of infection through a myelosuppressive effect. High clinical suspicion and early use of antimicrobials play a major role in decreasing any associated morbidity and mortality. This has led to a widespread use of antimicrobials in cancer patients. Antimicrobial use, however, does not come without its perils. Dysbiosis caused by antimicrobial use affects responses to chemotherapeutic agents and is prognostic in the development and severity of certain cancer treatment-related complications such as graft-versus-host disease and Clostridioides difficile infections. Studies have also demonstrated that an intact gut microbiota is essential in the anticancer immune response. Antimicrobial use can therefore modulate responses and outcomes with immunotherapy targeting immune checkpoints. In this review, we highlight the perils associated with antimicrobial use during cancer therapy and the importance of a more judicious approach. We discuss the nature of the pathologic changes in the gut microbiota resulting from antimicrobial use. We explore the effect these changes have on responses and outcomes to different cancer treatment modalities including chemotherapy and immunotherapy, as well as potential adverse clinical consequences in the setting of stem cell transplant.

Spatiotemporal presentation of exogenous SDF-1 with PLGA nanoparticles modulates SDF-1/CXCR4 signaling axis in the rodent cortex.

Stromal cell-derived factor-1 (SDF-1) and its key receptor CXCR4 have been implicated in directing cellular recruitment for several pathological/disease conditions thus also gained considerable attention for regenerative medicine. One regenerative approach includes sustained release of SDF-1 to stimulate prolonged stem cell recruitment. However, the impact of SDF-1 sustained release on the endogenous SDF-1/CXCR4 signaling axis is largely unknown as auto-regulatory mechanisms typically dictate cytokine/receptor signaling. We hypothesize that spatiotemporal presentation of exogenous SDF-1 is a key factor in achieving long-term manipulation of endogenous SDF-1/CXCR4 signaling. Here in the present study, we sought to probe our hypothesis using a transgenic mouse model to contrast the spatial activation of endogenous SDF-1 and CXCR4 in response to exogenous SDF-1 injected in bolus or controlled release (PLGA nanoparticles) form in the adult rodent cortex. Our data suggests that the manner of SDF-1 presentation significantly affected initial CXCR4 cellular activation/recruitment despite having similar protein payloads over the first 24 h (∼30 ng for both bolus and sustained release groups). Yet, one week post-injection, this response was negligible. Therefore, the transient nature CXCR4 recruitment/activation in response to bolus or controlled release SDF-1 indicated that cytokine/receptor auto-regulatory mechanisms may demand more complex release profiles (i.e. delayed and/or pulsed release) to achieve sustained cellular response.

Tunable delayed controlled release profile from layered polymeric microparticles.

Composite microparticles (MPs) with layered architecture, engineered from poly(L-lactic acid) (PLLA) and poly(D,L-lactic-co-glycolic acid) (PLGA), are promising devices for achieving the delayed release of proteins. Here, we build on a water-in-oil-in-oil-in-water emulsion method of fabricating layered MPs with an emphasis on modulating the delay period of the protein release profile. Particle hardening parameters (i.e. polymer precipitation rate and total hardening time) following water-in-oil-in-oil-in-water emulsions are known to affect MP structure such as the core/shell material and cargo localization. We demonstrate that layered MPs fabricated with two different solvent evaporation parameters not only alter polymer and protein distribution within the hardened MPs, but also affect their protein release profiles. Secondly, we hypothesize that ethanol (EtOH), a semi-polar solvent miscible in both the solvent (dichloromethane; DCM) and non-solvent aqueous phases, likely alters DCM and water flux from the dispersed oil phase. The results reveal that EtOH affects protein distribution within MPs, and may also influence MP structural properties such as porosity and polymer distribution. To our knowledge, we are the first to demonstrate EtOH as a means for modulating critical release parameters from protein-loaded, layered PLGA/PLLA MPs. Throughout all the groups in the study, we achieved differential delay periods (between 0 - 30 days after an initial burst release) and total protein release periods (~30 - >58 days) as a function of solvent evaporation parameters and EtOH content. The layered MPs proposed in the study potentially have wide-reaching applications in tissue engineering for delayed and sequential protein release.

Mortality on the Kidney Waiting List and After Transplantation in Patients With Peripheral Arterial Disease: An Analysis of the United States Renal Data System.

BACKGROUND: Reports from the United States Renal Data System (USRDS) indicated that kidney transplantation, whether from a living donor (LD) or deceased donor (DD), offers survival advantage over being on the waiting list. Whether this is true for patients with peripheral arterial disease (PAD) is unknown given that patients with PAD have significant comorbidities. METHODS: We used a cohort of USRDS incident dialysis patients from 2001 to 2007, with follow-up through 2008. Patients with PAD younger than the age of 70 were included and divided into 3 groups; PAD waitlisted, PAD patients who received a first transplant from a DD, or PAD patients who received a first transplant from a LD. Time-dependent Cox regression models were used to compare differences in mortality. RESULTS: In this study, 23,699 incident dialysis patients met inclusion criteria; only 16.7% (n = 3964) were waitlisted, of which 8.9 % (n = 2121) underwent transplantation. Patient survival in the LD group at any time point was significantly better than being on the waiting list (P < .001). For DD, mortality was higher in the first year compared with waitlisted patients (P < .001), however, after 1 year survival did not differ as compared with remaining on the waiting list. After adjusting for confounders, the relative risk (RR) of dying was significantly higher for patients with history of severe vascular disease requiring amputation (RR, 1.45; 95% confidence interval [CI], 1.15-1.84) in the DD group. CONCLUSIONS: Kidney transplantation from a DD did not offer survival advantage over being on the waiting list, in part due to a higher rate of severe vascular disease. Careful patient selection may improve outcomes in the DD group.

Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides.

Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D-Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events.

Evaluation of non-adherence in patients undergoing dialysis and kidney transplantation: United States transplantation practice patterns survey.

INTRODUCTION: We performed a survey of United States transplantation centers to evaluate practice patterns in the assessment of nonadherence before and after kidney transplantation. METHODS: An electronically administered, anonymous survey was sent to 181 United Network for Organ Sharing (UNOS) approved transplantation centers in 2012. RESULTS: Seventy-nine centers completed our survey. Of them, 51.3% had a protocol to evaluate medication/dialysis adherence before the listing; most common (36.4%) was the Simplified Medication Adherence Questionnaire. As an alternative to a questionnaire, the most common measure of nonadherence was the number of missed hemodialysis sessions (77.0%). The most common reason for poor adherence to dialysis regimens was difficulty with transportation (81.3%). Also, 94.4% noted the lack of a questionnaire to evaluate adherence to medications but relied on drug levels (73.4%) and self report. Only 12.9% used a questionnaire for the measurement of quality of life (Karnofsky performance scale). Of the participating centers, 27.1% used a formal cognitive testing for potential living donors. A social worker was used by most centers for nonadherent patients. Respondents indicated that patients (in the pretransplantation state) were more compliant with dialysis than with medication regimens. Finally, 37.7% of respondents noted graft failure due to medication nonadherence in 15% to 29% of their patients. CONCLUSIONS: There was a significant variability in the methods of screening for nonadherence while the patient was on dialysis, during pretransplantation work up, and during post-transplantation follow-up examinations. We recommend that there should be a standardized technique to evaluate nonadherence to facilitate focused clinical trials to improve adherence.

Impact of human leukocyte antigen-DR mismatch status on kidney graft survival in a predominantly African-American population under the newer immunosuppressive era.

BACKGROUND: Human leukocyte antigen (HLA)-DR has been shown to be immunogenic and associated with poor long-term graft function. However, under potent induction immunosuppression with antithymocyte globulin, the impact of the HLA-DR remains unclear. METHOD: We reviewed 672 renal transplant recipients who received their transplants between 1998 and 2007. All patients received antithymocyte globulin as induction therapy followed by tacrolimus + prednisone + mycophenolate mofetil for maintenance immunosuppression. We divided the patients into three groups according to HLA-DR mismatch status (zero, one, or two mismatches). RESULTS: The three groups were different in total number of mismatches, deceased donor transplant, and delayed graft function, respectively. By Kaplan-Meier survival analysis, actuarial graft survival was significantly lower in the HLA-DR two mismatches group (72%) compared to HLA-DR zero mismatches group (78.5%) or HLA-DR one mismatch group (78.5%; P = .05, by log-rank test). Using Cox regression analysis, the risk of graft failure with two HLA-DR mismatches as compared with zero HLA-DR mismatches was 1.6 (95% confidence interval = 1.0-2.44, P = .049). When adjusted for age, wait time, race, type of transplant, retransplant status, T-cell flow crossmatch, delayed graft function, acute rejection, HLA-A and HLA-B, the effect of HLA-DR on survival was not significant (P = .55). CONCLUSION: The independent effect of HLA-DR mismatches on adverse graft survival is diminished under potent antibody induction and maintenance immunosuppression in our predominantly African-American population.

A new method to control ultrafiltration in conventional continuous renal replacement therapy.

Conventional continuous arteriovenous hemofiltration/hemodialysis (CAVH/D) and slow continuous ultrafiltration (SCUF) are types of continuous renal replacement therapy (CRRT) in which the ultrafiltrate (UF) volume is controlled imprecisely with a UF clamp, which is labor intensive, demanding frequent adjustment to preclude excessive fluid removal. We devised a simple method for precise control of the UF volume. Seven CRRTs in the form of CAVH, CAVHD, and SCUF were performed in four patients with massive edema. A standard circuit was created in each case using blood tubing sets and an HF 400 hemofilter obtained from MinnTech. Standard intravenous infusion tubing connected to an infusion pump (IMED, Gemini PC-2 volumetric pump/controller) with its proximal end inserted into the dialysate port at the venous end of the hemofilter, and the distal end draining into a plastic bag, was used to control the UF rate. Dialysis was added to the circuit using another pump connected to the dialysate port at the arterial end of the hemofilter. Treatment time ranged from 27 to 78 hours. Target fluid removal was achieved in all treatments, and the net UF rate required only once daily adjustment for total fluid intake. Mean time to reporting a problem by the intensive care nurse was 30 hours (range, 25-30 hours), and mean time to filter clotting was 38 hours (range, 27-40 hours). This set-up is less labor intensive, more cost effective, and is applicable in areas lacking automated machines. Future development of tubing for UF designed as above may further reduce cost.

Common iliac artery stenosis presenting as renal allograft dysfunction in two diabetic recipients.

BACKGROUND: Suprarenal common iliac artery stenosis is an uncommon but reversible cause of allograft dysfunction in renal transplant recipients. METHOD: We describe two diabetic renal transplant recipients with worsening hypertension, edema, and azotemia. Magnetic resonance angiography (MRA) demonstrated tight stenoses in the common iliac artery proximal to the allograft anastomosis site with patent renal transplant artery in both cases. These findings were later confirmed with carbon dioxide angiography. RESULTS: No acute rejection was noted on renal biopsy in either case. Placement of percutaneous iliac artery Wallstents resulted in decrease of serum creatinine from 6.5 to 2.0 mg/dl and 1.7 to 1.0 mg/dl within 2 and 4 weeks, respectively. CONCLUSION: Common iliac artery stenosis should be suspected in renal transplant recipients presenting with worsening hypertension, edema and azotemia. MRA for screening followed by carbon dioxide angiography and placement of intravascular stents for focal vascular obstructive lesions reverses allograft dysfunction.

Bilateral renal infarction in a black man with medial fibromuscular dysplasia.

We report a case of bilateral renal infarction in a patient with medial fibrous dysplasia of both renal arteries and a thrombosed aneurysmal dilatation of the right renal artery. A previously healthy 40-year-old black man presented to the emergency department with acute onset of bilateral flank pain. Computerized tomography of the abdomen showed bilateral renal infarction, predominantly affecting the anterior distribution of both renal arteries. Estimated loss of renal mass was 50% on the right and 25% on the left. The patient was treated with intravenous heparin, oral warfarin, and antihypertensive therapy with labetolol and long-acting nifedipine. By day 3, his abdominal pain resolved; however, the serum creatinine level increased to a maximum value of 2.6 mg/dL. The serum creatinine level slowly improved and stabilized at 1.9 mg/dL, and he was subsequently discharged on the seventh hospital day. Magnetic resonance angiography performed 2 months later showed "beading2 of both renal arteries consistent with medial fibromuscular dysplasia, a finding confirmed by conventional angiography. To our knowledge, bilateral renal infarction complicating medial fibrous dysplasia of the renal arteries has not been previously reported, nor has medial fibrous dysplasia been reported in blacks.

Cloning of the human platelet F11 receptor: a cell adhesion molecule member of the immunoglobulin superfamily involved in platelet aggregation.

This study demonstrates that the human platelet F11 receptor (F11R) functions as an adhesion molecule, and this finding is confirmed by the structure of the protein as revealed by molecular cloning. The F11R is a 32-/35-kd protein duplex that serves as the binding site through which a stimulatory monoclonal antibody causes platelet aggregation and granule secretion. A physiological role for the F11R protein was demonstrated by its phosphorylation after the stimulation of platelets by thrombin and collagen. A pathophysiological role for the F11R was revealed by demonstrating the presence of F11R-antibodies in patients with thrombocytopenia. Adhesion of platelets through the F11R resulted in events characteristic of the action of cell adhesion molecules (CAMs). To determine the structure of this protein, we cloned the F11R cDNA from human platelets. The predicted amino acid sequence demonstrated that it is an integral membrane protein and an immunoglobulin superfamily member containing 2 extracellular C2-type domains. The structure of the F11R as a member of a CAM family of proteins and its activity in mediating adhesion confirm each another. We conclude that the F11R is a platelet-membrane protein involved in 2 distinct processes initiated on the platelet surface. The first is antibody-induced platelet aggregation and secretion that are dependent on both the FcgammaRII and the GPIIb/IIIa integrin and that may be involved in pathophysiological processes associated with certain thrombocytopenias. The second is an F11R-mediated platelet adhesion that is not dependent on either the FcgammaRII or the fibrinogen receptor and that appears to play a role in physiological processes associated with platelet adhesion and aggregation. (Blood. 2000;95:2600-2609)

Enhancement of human platelet aggregation and secretion induced by rapamycin.

BACKGROUND: Rapamycin is a new immunosuppressive drug of the macrolide type. Despite binding to one of the FK-binding proteins as the initial step in intracellular action, further effects differ from those of the other fungally derived macrolides, cyclosporine and tacrolimus. We have previously demonstrated an enhancement of agonist-mediated platelet activation by cyclosporine and tacrolimus which was associated with increased phosphorylation of two intracellular platelet proteins, p20 and p40. Because rapamycin utilizes the same class of binding proteins as tacrolimus, but its action is not associated with the inhibition of calcineurin, we postulated that if the stimulatory effect of cyclosporine or tacrolimus was due to calcineurin inhibition, rapamycin should not affect platelets in a similar fashion. METHODS: Normal, washed human platelets were treated with various concentrations of rapamycin (from ng to microg/ml), and pre-incubated at 37 degrees C with rapamycin for various periods (1-30 min). Several platelet functional parameters were measured in samples treated with rapamycin and these parameters were compared with control platelet samples treated with the vehicle for the same period. Platelet aggregations following exposure to ADP or to the thrombin equivalent, TRAP-6, were measured as changes in optical transmission in a Chronolog lumi-aggregometer. Each experiment was repeated at three or more times and the mean results were used for statistical comparison. RESULTS: Rapamycin-treated platelets demonstrated an increase in their dose- and time-dependent sensitivity to ADP, resulting in a significantly enhanced primary wave of ADP-induced platelet aggregation followed by a secondary wave of aggregation, indicative of granule secretion. Furthermore, rapamycin-treated platelets showed significantly enhanced sensitivity to TRAP-6 as demonstrated by an increase in the initial velocity of aggregation, an increase in their maximal extent of aggregation and an enhancement of granular ATP secretion. Concentrations of rapamycin in the ng range, as well as short pre-incubation times (within min), were sufficient to cause significant enhancement of agonist-induced platelet aggregation and secretion (P < 0.001) as compared with their vehicle controls. CONCLUSIONS: Rapamycin significantly potentiates agonist-induced platelet aggregation in a time- and dose-dependent manner. As these findings are similar to those observed with the other fungal macrolides, we hypothesize that inhibition of calcineurin may not be necessary for the increase in intracellular protein phosphorylation observed following exposure of platelets to cyclosporine or tacrolimus. Whether the rapamycin-induced enhancement of sensitivity to agonists and platelet hyperaggregability explains the thrombocytopenia observed in patients when high doses of rapamycin are administered in the clinical setting, and whether these effects are synergistic with cyclosporine, are questions which remain to be investigated.