Functional outcomes of pediatric laparoscopic pyeloplasty: post-operative functional recovery is superior in infants compared to older children.

AIM: Laparoscopic pyeloplasty (LP) is less popular and considered less successful in infants compared to older children. There are few reports analyzing the functional results of LP in relation to age of surgery. The aim of this paper is to compare the functional results of LP in infants (group 1) with children over 1 year of age (group 2). MATERIAL AND METHODS: The data of all children undergoing LP between August 2016 and July 2019 were retrospectively analyzed for patient details and follow-up. Only children (n = 135) with at least 1-year follow-up and completed post-operative ultrasound and diuretic renogram were included. All children underwent pre-operative and post-operative ultrasound and diuretic renogram; pre-operative, operative and post-operative parameters were compared between both groups. Statistical analysis was done using software; Mann-Whitney U test, Student t test, and Fisher's exact test were applied. RESULTS: There were 71 infants (group 1) and 64 children > 1 year (group 2). Pre-operatively, all kidneys had SFU grade 3 or 4 HDN and 131/135 kidneys had a renal pelvic APD > 20 mm; all kidneys had unequivocal obstruction on DR. At surgery, the preferred drainage method was intra-operative antegrade placement of a JJ stent in 68 (96%) group 1 and 63 (98%) group 2 children. The remaining 4 cases (3 group 1, 1 group 2) had a nephrostomy with trans-anastomotic external stent placement, because the JJ stent could not be negotiated into the bladder. The demographic data and comparison of pre- and post-operative parameters between both groups are summarized in Tables 1 and 2, respectively. Group 1 had significantly more children with antenatal diagnosis of HDN (87% vs 56%, p = 0.0005). The 36 children with antenatal diagnosis in group 2 were initially followed expectantly; the indication for pyeloplasty was deterioration of SRF on serial DR, urinary infection, and pain, in 13, 14, and 9 children, respectively. The operating time was significantly longer in group 2 (p = 0.0001). There was no difference in the success of LP or complication rate in both groups. Group 2 had significantly more children with extrinsic obstruction (1.4% vs 17%, p = 0.001). All children underwent post-operative US and DR; a significant reduction in hydronephrosis (APD) on follow-up was noted in both groups (p = 0.0001). The mean pre-operative SRF in both groups was comparable (p = 0.088). The mean SRF in both groups improved significantly after LP; however, the mean post-operative SRF was significantly higher in group 1 when compared to group 2 (p = 0.0001). Furthermore, group 1 had significantly more kidneys demonstrating > 10% increase in SRF after LP (53% vs 26%, p = 0.0003). CONCLUSIONS: The safety profile and success of LP in infants was comparable to older children. Infant LP took shorter time to perform, while older children had increased incidence of extrinsic obstruction. Infant kidneys demonstrated better functional improvement than older children after LP. These findings should encourage more surgeons to utilize LP for pyeloplasty even in infants.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.

Predictable hematological markers associated with cognitive decline in valid rodent models of cognitive impairment.

Endogenous (hyperglycemia) and exogenous (therapeutic, prophylactic, street drugs) factors can considerably contribute to cognitive impairment (CI). Currently, there are few invasive and/or noninvasive markers that correlate with CI and those that do exist require expensive or invasive techniques to predict and accurately measure the cognitive decline. Therefore, we sought to determine hematological markers as predictors of CI in two different chemically induced valid rodent models of CI (streptozotocin induced hyperglycemic model and chemotherapy [doxorubicin/cyclophosphamide] treated rodent model). Hematological markers were analyzed in the above rodent models of CI CI and compared to their respective control groups. There was a significant increase in creatinine kinase, lactate dehydrogenase and aspartate aminotransferase (AST) in the chemotherapy group. Blood urea nitrogen (BUN), alkaline phosphatase (ALP), bilirubin, creatinine and glucose levels were significantly increased in the streptozotocin group. Interestingly, triglycerides were significantly elevated in both the streptozotocin and chemotherapy groups. Previous studies with human subjects have shown a potential link between the increase in triglyceride levels and CI. Likewise, our data indicate a notable correlation with an increase in triglycerides to cognitive impairment in the rodent models. This suggests elevated levels of triglycerides could prove to be a potential noninvasive hematological marker for the increased risk of CI. Further studies are warranted to determine the causal relationship between elevated triglyceride levels and CI.

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression.

Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochrome P450/drug transporters can be reversed with the use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack the specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, an hPXR antagonist would be a cancer drug itself that is part of a "cancer drug cocktail" and effective as an hPXR antagonist at therapeutic concentrations. Belinostat (BEL), a histone deacetylase inhibitor approved for the treatment of relapsed/refractory peripheral T-cell lymphoma, and often used in combination with chemotherapy, is an attractive candidate based on its hPXR ligand-like features. We sought to determine whether these features of BEL might allow it to behave as an antagonist in combination chemotherapy regimens that include hPXR activators. BEL represses agonist-activated hPXR target gene expression at its therapeutic concentrations in human primary hepatocytes and LS174T human colon cancer cells. BEL repressed rifampicin-induced gene expression of CYP3A4 and multidrug resistance protein 1, as well as their respective protein activities. BEL decreased rifampicin-induced resistance to SN-38, the active metabolite of irinotecan, in LS174T cells. This finding indicates that BEL could suppress hPXR agonist-induced chemoresistance. BEL attenuated the agonist-induced steroid receptor coactivator-1 interaction with hPXR, and, together with molecular docking studies, the study suggests that BEL directly interacts with multiple sites on hPXR. Taken together, our results suggest that BEL, at its clinically relevant therapeutic concentration, can antagonize hPXR agonist-induced gene expression and chemoresistance.

Meta-analysis of transfemoral TAVR versus surgical aortic valve replacement.

BACKGROUND: In the recently concluded PARTNER 2 trial, TF-TAVR cohort was shown to have lower risks of death or disabling strokes as compared to SAVR, whereas the outcomes with transthoracic TAVR were comparable with SAVR. METHODS: We searched PubMed, EMBASE, Web of Science, and Google Scholar for all comparison studies between TAVR and SAVR and mortality as an outcome, irrespective of surgical risk. Randomized controlled trials and propensity-score-matched cohort studies that used a transfemoral approach exclusively or stratified results by route of access and reported data for TF-TAVR patients were eligible for inclusion. Outcomes of interest included 30-day and 1-year mortality, and 30-day complications. If significant heterogeneity was found in the random effects meta-analyses, a sensitivity analysis which individually removed each study was conducted. RESULTS: Seven studies reported results on TF-TAVR. Compared with SAVR, TF-TAVR had comparable 30-day mortality (RR 0.79, 95% CI 0.58, 1.06), 1-year mortality (RR 0.91, 95% CI 0.78, 1.08) and 30-day risk of bleeding (RR 0.70, 95% CI 0.31, 1.57). However, TF-TAVR was associated with lower 30-day risks of atrial fibrillation (RR 0.28, 95% CI 0.17, 0.45), acute kidney injury (RR 0.38, 95% CI 0.20, 0.71), and myocardial infarction (RR 0.41, 95% CI 0.23, 0.75) at a cost of higher incidences of vascular complications (RR 6.10, 95% CI 2.92, 12.73) and pacemaker implantations (RR 3.29, 95% CI 1.41, 7.65). CONCLUSIONS: TF-TAVR is associated with lower 30-day risks of myocardial infarction compared to SAVR. Further studies are required to investigate the role of myocardial injury on overall TF-TAVR outcomes.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Lower Surgical Risk Scores: A Systematic Review and Meta-Analysis of Early Outcomes.

BACKGROUND: The results from the PARTNER 2 trial showed the feasibility of transcatheter aortic valve replacement (TAVR) in intermediate surgical risk patients. Although low risk clinical trials will take time to conclude, some data has emerged comparing TAVR with surgical aortic valve replacement (SAVR) in lower risk patients. METHODS: A Medline search was conducted using standard methodology to search for studies reporting results comparing TAVR and SAVR. Studies were included if the overall mean Society of Thoracic Surgeons Score was less than 4% (or equivalent Euroscore). A meta-analysis comparing the 30-day risk of clinical outcomes between TAVR and SAVR in the lower surgical risk population was conducted. RESULTS: A total of four studies, including one clinical trial and three propensity-matched cohort studies met the inclusion criteria. Compared to SAVR, TAVR had a lower risk of 30-day mortality (RR 0.67, 95% CI 0.41, 1.10), stroke (RR 0.60, 95% CI 0.30, 1.22), bleeding complications (RR 0.51, 95% CI 0.40, 0.67) and acute kidney injury (RR 0.66, 95% CI 0.47, 0.94). However, a higher risk of vascular complications (RR 11.72, 95% CI 3.75, 36.64), moderate or severe paravalvular leak (RR 5.04, 95% CI 3.01, 8.43), and permanent pacemaker implantations (RR 4.62, 95% CI 2.63, 8.12) was noted for TAVR. CONCLUSION: Among lower risk patients, TAVR and SAVR appear to be comparable in short term outcomes. Additional high quality studies among patients classified as low risk are needed to further explore the feasibility of TAVR in all surgical risk patients.

Stearidonic acid, a plant-based dietary fatty acid, enhances the chemosensitivity of canine lymphoid tumor cells.

Lymphoma is the most common hematopoietic tumor in dogs and humans, with similar pathogenesis and therapeutic responses. Anticancer drugs like vincristine (VCR) and doxorubicin (DOX) are often used in treating lymphoma. However, the cure rate is generally poor due to chemoresistance. Here, we sought to determine whether stearidonic acid (SDA), a plant-based dietary fatty acid, sensitizes chemoresistant canine lymphoid-tumor cells. GL-1 B-cell lymphoid-tumor cells were found to be highly sensitive to the antitumor-activity of VCR and DOX, while OSW T-cell and 17-71 B-cell lymphoid-tumor cells were moderately and fully resistant, respectively. SDA, at its non-toxic concentrations, significantly promoted the antitumor action of VCR and DOX in both OSW and 17-71 cells. SDA-mediated chemosensitization was associated with SDA inhibition of P-glycoprotein (P-gp) function. This was confirmed in HEK293 cells stably expressing P-gp as well as by increased binding-affinity of SDA to P-gp in P-gp docking analysis. SDA at its chemosensitizing concentrations did not affect the viability of healthy dog peripheral blood mononuclear cells, suggesting that SDA is non-toxic to normal dog peripheral blood leucocytes at its chemosensitizing concentrations. Our study identifies a novel dietary fatty acid that may be used as a dietary supplement in combination with chemotherapy to promote the antitumor efficacy of the chemotherapy drugs in dogs and possibly in humans with chemoresistant lymphoma.

Mg2+/Mn2+-dependent phosphatase 1A is involved in regulating pregnane X receptor-mediated cytochrome p450 3A4 gene expression.

Variations in the expression of human pregnane X receptor (hPXR)-mediated cytochrome p450 3A4 (CYP3A4) in liver can alter therapeutic response to a variety of drugs and may lead to potential adverse drug interactions. We sought to determine whether Mg(2+)/Mn(2+)-dependent phosphatase 1A (PPM1A) regulates hPXR-mediated CYP3A4 expression. PPM1A was found to be coimmunoprecipitated with hPXR. Genetic or pharmacologic activation of PPM1A led to a significant increase in hPXR transactivation of CYP3A4 promoter activity. In contrast, knockdown of endogenous PPM1A not only attenuated hPXR transactivation, but also increased proliferation of HepG2 human liver carcinoma cells, suggesting that PPM1A expression levels regulate hPXR, and that PPM1A expression is regulated in a proliferation-dependent manner. Indeed, PPM1A expression and hPXR transactivation were found to be significantly reduced in subconfluent HepG2 cells compared with confluent HepG2 cells, suggesting that both PPM1A expression and hPXR-mediated CYP3A4 expression may be downregulated in proliferating livers. Elevated PPM1A levels led to attenuation of hPXR inhibition by tumor necrosis factor-α and cyclin-dependent kinase-2, which are known to be upregulated and essential during liver regeneration. In mouse regenerating livers, similar to subconfluent HepG2 cells, expression of both PPM1A and the mouse PXR target gene cyp3a11 was found to be downregulated. Our results show that PPM1A can positively regulate PXR activity by counteracting PXR inhibitory signaling pathways that play a major role in liver regeneration. These results implicate a novel role for PPM1A in regulating hPXR-mediated CYP3A4 expression in hepatocytes and may explain a mechanism for CYP3A repression in regenerating livers.

IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells.

Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.

Current status of robotic and laparoscopic techniques in radical cystectomy and diversion procedures for bladder cancer: review.

Across the world there has been an increased interest in minimally invasive approaches in extirpative and reconstructive surgery for bladder cancer. Minimally invasive approaches i.e. robotic and pure laparoscopic radical cystectomy have the greatest advantage of reduced blood loss, postoperative pain, quicker recovery of bowel function and earlier convalescence. Compared to established open techniques, there have been increasing reports of equivalent oncologic out comes and reduced complication rates in short and intermediate follow-ups. There have been several reports on urinary diversions achieved through minimal invasion and there is increasing interest to perform with robotic assistance. This review aims to review the currently published literature, technical aspects of the procedure, perioperative, oncologic and functional outcomes.

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells.

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells. Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo. Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.

The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.

Effects of Cannabidiol, ∆9-Tetrahydrocannabinol, and WIN 55-212-22 on the Viability of Canine and Human Non-Hodgkin Lymphoma Cell Lines.

In our previous study, we demonstrated the impact of overexpression of CB1 and CB2 cannabinoid receptors and the inhibitory effect of endocannabinoids (2-arachidonoylglycerol (2-AG) and Anandamide (AEA)) on canine (Canis lupus familiaris) and human (Homo sapiens) non-Hodgkin lymphoma (NHL) cell lines' viability compared to cells treated with a vehicle. The purpose of this study was to demonstrate the anti-cancer effects of the phytocannabinoids, cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), and the synthetic cannabinoid WIN 55-212-22 (WIN) in canine and human lymphoma cell lines and to compare their inhibitory effect to that of endocannabinoids. We used malignant canine B-cell lymphoma (BCL) (1771 and CLB-L1) and T-cell lymphoma (TCL) (CL-1) cell lines, and human BCL cell line (RAMOS). Our cell viability assay results demonstrated, compared to the controls, a biphasic effect (concentration range from 0.5 µM to 50 µM) with a significant reduction in cancer viability for both phytocannabinoids and the synthetic cannabinoid. However, the decrease in cell viability in the TCL CL-1 line was limited to CBD. The results of the biochemical analysis using the 1771 BCL cell line revealed a significant increase in markers of oxidative stress, inflammation, and apoptosis, and a decrease in markers of mitochondrial function in cells treated with the exogenous cannabinoids compared to the control. Based on the IC50 values, CBD was the most potent phytocannabinoid in reducing lymphoma cell viability in 1771, Ramos, and CL-1. Previously, we demonstrated the endocannabinoid AEA to be more potent than 2-AG. Our study suggests that future studies should use CBD and AEA for further cannabinoid testing as they might reduce tumor burden in malignant NHL of canines and humans.

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons.

BACKGROUND: Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. AIM: This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. METHODS AND RESULTS: Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. CONCLUSION: This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.

cAMP-stimulated Cl- secretion is increased by glucocorticoids and inhibited by bumetanide in semicircular canal duct epithelium.

BACKGROUND: The vestibular system controls the ion composition of its luminal fluid through several epithelial cell transport mechanisms under hormonal regulation. The semicircular canal duct (SCCD) epithelium has been shown to secrete Cl- under ß2-adrenergic stimulation. In the current study, we sought to determine the ion transporters involved in Cl- secretion and whether secretion is regulated by PKA and glucocorticoids. RESULTS: Short circuit current (Isc) from rat SCCD epithelia demonstrated stimulation by forskolin (EC50: 0.8 µM), 8-Br-cAMP (EC50: 180 µM), 8-pCPT-cAMP (100 µM), IBMX (250 µM), and RO-20-1724 (100 µM). The PKA activator N6-BNZ-cAMP (0.1, 0.3 & 1 mM) also stimulated Isc. Partial inhibition of stimulated Isc individually by bumetanide (10 & 50 µM), and [(dihydroindenyl)oxy]alkanoic acid (DIOA, 100 µM) were additive and complete. Stimulated Isc was also partially inhibited by CFTRinh-172 (5 & 30 µM), flufenamic acid (5 µM) and diphenylamine-2,2'-dicarboxylic acid (DPC; 1 mM). Native canals of CFTR+/- mice showed a stimulation of Isc from isoproterenol and forskolin+IBMX but not in the presence of both bumetanide and DIOA, while canals from CFTR-/- mice had no responses. Nonetheless, CFTR-/- mice showed no difference from CFTR+/- mice in their ability to balance (rota-rod). Stimulated Isc was greater after chronic incubation (24 hr) with the glucocorticoids dexamethasone (0.1 & 0.3 µM), prednisolone (0.3, 1 & 3 µM), hydrocortisone (0.01, 0.1 & 1 µM), and corticosterone (0.1 & 1 µM) and mineralocorticoid aldosterone (1 µM). Steroid action was blocked by mifepristone but not by spironolactone, indicating all the steroids activated the glucocorticoid, but not mineralocorticoid, receptor. Expression of transcripts for CFTR; for KCC1, KCC3a, KCC3b and KCC4, but not KCC2; for NKCC1 but not NKCC2 and for WNK1 but only very low WNK4 was determined. CONCLUSIONS: These results are consistent with a model of Cl- secretion whereby Cl- is taken up across the basolateral membrane by a Na+-K+-2Cl- cotransporter (NKCC) and potentially another transporter, is secreted across the apical membrane via a Cl- channel, likely CFTR, and demonstrate the regulation of Cl- secretion by protein kinase A and glucocorticoids.

Effects of developmental exposures to Bisphenol-A and Bisphenol-S on hepatocellular function in male Long-Evans rats.

Bisphenol-S (BPS) is a current substitute for Bisphenol-A (BPA) in various commercial products (paper, plastics, protective can-coatings, etc.) used by all age groups globally. The current literature indicates that a drastic surge in pro-oxidants, pro-apoptotic, and pro-inflammatory biomarkers in combination with diminished mitochondrial activity can potentially decrease hepatic function leading to morbidity and mortality. Consequently, there are increasing public health concerns that substantial Bisphenol-mediated effects may impact hepatocellular functions, particularly in newborns exposed to BPA and BPS postnatally. However, the acute postnatal impact of BPA and BPS and the molecular mechanisms affecting hepatocellular functions are unknown. Therefore, the current study investigated the acute postnatal effect of BPA and BPS on the biomarkers of hepatocellular functions, including oxidative stress, inflammation, apoptosis, and mitochondrial activity in male Long-Evans rats. BPA and BPS (5 and 20 microgram/Liter (µg/L) of drinking water) were administered to 21-day-old male rats for 14 days. BPS had no significant effect on apoptosis, inflammation, and mitochondrial function but significantly reduced the reactive oxygen species (51-60 %, **p < 0.01) and nitrite content (36 %, *p < 0.05), exhibiting hepatoprotective effects. As expected, based on the current scientific literature, BPA induced significant hepatoxicity, as seen by significant glutathione depletion (50 %, *p < 0.05). The in-silico analysis indicated that BPS is effectively absorbed in the gastrointestinal tract without crossing the blood-brain barrier (whereas BPA crosses the blood-brain barrier) and is not a substrate of p-Glycoprotein and Cytochrome P450 enzymes. Thus, the current in-silico and in vivo findings revealed that acute postnatal exposure to BPS had no significant hepatotoxicity.

Prevalence and Risk Factors for Iatrogenic Opioid Withdrawal in Medical Critical Care Patients.

Opioids are the mainstay of pain management and sedation in critically ill patients, which can lead to the development of physiologic tolerance and dependency. The prevalence of iatrogenic opioid withdrawal syndrome (IWS) is reported as 17-32% in the ICU; however, limited evidence exists for the medical ICU patient population. OBJECTIVES: To identify the and risk factors for IWS in adult patients admitted to critical care medicine services who received greater than or equal to 24 hours of continuous opioid infusion therapy. DESIGN SETTING AND PARTICIPANTS: A prospective, observational study was conducted in a tertiary care hospital in adult medical ICU patients. Ninety-two patients who received greater than or equal to 24 hours of continuous opioid infusions were included in the study. MAIN OUTCOMES AND MEASUREMENTS: Patients were assessed daily after opioid infusion discontinuation using the Clinical Opiate Withdrawal Scale (COWS) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) opioid withdrawal criteria for a maximum of 5 days. The primary outcome was the prevalence of IWS of moderate severity or greater using COWS. Secondary outcomes included the prevalence of IWS diagnosis of any severity based on COWS, the prevalence of IWS diagnosis based on a positive DSM-V score, and the identification of potential risk factors for developing IWS of any severity. RESULTS: Four hundred forty-seven patients received greater than or equal to 24 hours of continuous opioid therapy. Of these, 385 were excluded, leaving 92 patients included in the final analysis. Except for a higher prevalence of psychiatric history in the IWS-positive group, baseline characteristics were similar. Overall, 11 patients (12%) developed IWS of moderate severity or greater, based on COWS. The IWS-positive group also had longer durations of opioid infusions, higher cumulative opioid infusion doses, higher mean daily doses, and higher infusion rates at any given time. The concomitant use of dexmedetomidine (38.3 vs 15.6%, p = 0.014) and benzodiazepines (63.8 vs 37.8%, p = 0.021) during or after the opioid infusion were significantly higher in the IWS-positive group compared with the IWS-negative group. No significant differences were found between the two groups for scheduled or as needed opioids after cessation of the opioid infusion. Continuous opioid infusions greater than or equal to 72 hours and total daily dose greater than or equal to 1,200 µg were found to be independent predictors for the development of iatrogenic opioid withdrawal via logistic regression. CONCLUSIONS AND RELEVANCE: Approximately one in every eight patients receiving continuous infusion opioid for greater than 24 hours while mechanically ventilated in the medical ICU will develop IWS of moderate severity or greater; this increases to one in three patients diagnosed with DSM-V criteria or any level of IWS severity. Patients receiving opioid infusions greater than or equal to 72 hours, or a total daily fentanyl dose of greater than or equal to 1,200 µg (~ 50 µg/hr) are at a higher risk for developing IWS and should be monitored as part of clinical practice when opioid infusions are discontinued.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Interplay between the Cannabinoid System and microRNAs in Cancer.

Cancer patients often use cannabinoids for alleviating symptoms induced by cancer pathogenesis and cancer treatment. This use of cannabinoids can have unexpected effects in cancer patients depending on the cancer type, resulting in either beneficial (e.g., anticancer) or adverse (e.g., oncogenic) effects. While cannabinoids can enhance the growth and progression of some cancers, they can also suppress the growth and progression of other cancers. However, the underlying mechanisms of such differential effects are poorly understood. miRNAs have been shown to be involved in driving the hallmarks of cancer, affecting cancer growth and progression as well as cancer therapy response. Although the understanding of the effects of cannabinoids and miRNAs as they relate to cancer continues to improve, the interplay between cannabinoid system and miRNAs in cancer pathogenesis and cancer treatment response is poorly understood. Investigation of such interactions between the cannabinoid system and miRNAs could provide novel insights into the underlying mechanisms of the differential effects of cannabinoids in cancer and can help predict and improve the prognosis of cancer patients.