Health-related quality of life and fear of progression in individuals with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome associated with a highly elevated lifetime cancer risk. This and the recommended intense surveillance program represent a large psychological burden on families. In order to develop targeted psychosocial interventions, we conducted a needs assessment. Adults (≥18 years) with LFS were included via regular hospital visits and online support groups and newsletters. Individuals filled out a questionnaire addressing among others: fear of progression (FoP-questionnaire, short-form), health-related quality of life (HRQoL, Short-Form Health Survey-12), distress (National Comprehensive Cancer Network distress thermometer), perceived cancer risk, and aspects of surveillance adherence. Collecting data over a 14-month period (March 2020 - June 2021), 70 adults were recruited (female = 58, 82.9%; mean age = 41.53 years). With mean mental component scores (MCS) of 42.28 (SD = 10.79), and physical component scores (PCS) of 48.83 (SD = 10.46), HRQoL was low in 34.8% (physical) and 59.4% (mental) of individuals when applying a mean cut-off of 45.4 (PCS) and 47.5 (MCS) to indicate poor HRQoL. High levels of FoP and distress were present in 68.6% and 69.1% of the participants, respectively. Performing a multiple linear regression on MCS and PCS, no sociodemographic variable was shown to be significant. FoP (ß = -0.33, p < 0.05) and distress (ß = -0.34, p < 0.05) were significantly associated with MCS. Individuals in our sample were burdened more than expected, with the majority reporting low levels of (mental) HRQoL, high distress, and FoP. Psychosocial support is necessary to help individuals with LFS (survivors as well as "previvors") increase their HRQoL, as it is crucial to survival.

Diagnostic Accuracy of MR Spectroscopic Imaging and 18F-FET PET for Identifying Glioma: A Biopsy-Controlled Hybrid PET/MRI Study.

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18F-FET uptake and the MRSI signals choline (Cho), N-acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18F-FET PET.

Systematic review with network meta-analysis: Risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease.

BACKGROUND: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age. AIMS: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis. METHODS: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473). CONCLUSIONS: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

Urinary Outcomes After Magnetic Resonance Imaging-Guided Whole-Gland Transurethral Ultrasound Ablation for Prostate Cancer: Comparison of Suprapubic Tube to Indwelling Urethral Catheter.

Background: MRI-guided transurethral ultrasound ablation (TULSA) is under investigation for whole-gland ablation of low- and intermediate-risk prostate cancer. The ideal method for post-TULSA bladder drainage through postoperative suprapubic tube (SPT) vs indwelling urethral catheter (UC) has not been established. The objective of this study was to evaluate urinary outcomes after whole-gland TULSA, comparing postoperative SPT with UC. Materials and Methods: Two-institution retrospective analysis of whole-gland TULSA for men with grade group 1 and 2 prostate cancer. One institution placed SPT at the time of TULSA with clamp trials (day 10) and removal once voiding. The second placed UC until void trial (day 7). Outcomes included the International Prostate Symptom Score (IPSS), urinary bother score, catheter reinsertion, stricture, clean intermittent catheterization (CIC), and incontinence. Results: Forty-five patients (median age 67) were analyzed. The UC cohort (N = 26) was older (p = 0.007) than the SPT cohort (N = 19) but with similar baseline prostate volumes, IPSS, and urinary bother scores. Patients receiving UC had fewer days with catheter (p = 0.013). Although UC patients suffered more lower urinary tract symptoms at 1-month post-TULSA, there was no significant difference between IPSS scores at baseline and 6 months after surgery regardless of urinary management strategy, although the UC group noted significantly decreased urinary bother. Rates of infection were similar between groups. Six strictures were observed overall, with more in the SPT group, although the difference was not significant (4/19 [21.1%] SPT; 2/26 [7.7%] UC). At 6 months, incontinence rates were low and similar between groups (2/19 [10.5%] SPT; 4/26 [15.4%] UC) and only one patient (UC) required CIC. Conclusions: Our overall findings suggest that SPT and UC are both acceptable options for postoperative bladder drainage after whole-gland TULSA, with statistically similar rates of urinary complications but a slightly different side effect profile.

Which Men Do or Do Not Achieve Long-Term Symptom Relief After Holmium Laser Enucleation of the Prostate (HoLEP): 11 Years of HoLEP Experience.

Purpose: Apart from the existing level-one evidence, few centers have reported on long-term outcomes after Holmium Laser Enucleation of the Prostate (HoLEP). Against this backdrop we aimed to report on our treatment experience and identify predictors of persistent/recurrent lower urinary tract symptoms (LUTS) after the procedure. Materials and Methods: From 2006 to 2017, 2566 men underwent HoLEP at our institution. Only patients with available, cross-sectional follow-up (F/u) ≥6 months were included. Perioperative and F/u characteristics were compared by duration of F/u in months (quartiles). Multivariable logistic regression models (MVAs) were used to identify predictors of persistent/recurring symptoms, defined as International Prostate Symptom Score (IPSS) >7 at F/u. Results: A total of 774 patients with a median age of 70 years (interquartile range [IQR] = 66-75), prostate volume of 80 mL (IQR = 60-105), American Society of Anesthesiologists score 2 (IQR = 2-3), IPSS of 19 (IQR = 14-24), and quality of life (QoL) of 4 (3-5) at the time of operation were analyzed. Median F/u was 52 months (IQR = 32-77), overall current median prostate-specific antigen was 0.91 mg/dL (0.5-1.8), median IPSS and QoL were 3 (IQR = 1-7) and 1 (IQR 0-2), respectively. LUTS medication was present in 20 patients (2.6%), 15 (2%) patients required reoperation, and permanent urinary incontinence was present in 17 (2.2%) patients. On MVA age at operation (odds ratio [OR] = 1.04; 95% confidence interval [CI], 1.01-1.1; p = 0.013), prostate volume (OR = 0.99 [95% CI, 0.98-0.99;], p = 0.003), body mass index (OR = 1.06 [95% CI, 1.0-1.1], p = 0.043), presence of indwelling catheter (OR = 0.51 [95% CI, 0.32-0.81], p = 0.004), and anticholinergics before procedure (OR = 1.74 [95% CI, 1.01-3.0], p = 0.046) were predictors of persistent/recurring symptoms. Conclusions: Our HoLEP experience confirms durable and profound symptom relief in the vast majority men. A small fraction of patients complained about subjective persistent/recurring LUTS stressing the need for proper patient selection and timing of surgical intervention.

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2tm1.Stw mouse, is lacking. In the present study, we performed an automated counting of oxytocin cells in the entire paraventricular nucleus of the hypothalamus of Magel2tm1.Stw and wild-type control mice and found a significant reduction in the caudal part, which represents the parvocellular subdivision. In addition, based on the recent discovery that some astrocytes express the oxytocin receptor (OTR), we performed detailed analysis of astrocyte numbers and morphology in various brain regions, and assessed expression levels of the astrocyte marker glial fibrillary acidic protein, which was significantly decreased in the hypothalamus, but not other brain regions in Magel2tm1.Stw mice. Finally, we analyzed the number of OTR-expressing astrocytes in various brain regions and found a significant reduction in the nucleus accumbens of Magel2tm1.Stw mice, as well as a sex-specific difference in the lateral septum. This study suggests a role for caudal paraventricular nucleus oxytocin neurons as well as OTR-expressing astrocytes in a mouse model of PWS, provides novel information about sex-specific expression of astrocytic OTRs, and presents several new brain regions containing OTR-expressing astrocytes in the mouse brain.

Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.

Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection.

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.

NADES Compounds Identified in Hypoxis hemerocallidea Corms during Dormancy.

Soaking Hypoxis hemerocallidea corms in distilled water improved the propagation and development of cormlets, suggesting the potential leaching-out of inhibitory chemical compounds. To investigate the presence of inhibitory compounds, nuclear magnetic resonance (NMR) spectral data of the leachate from dormant H. hemerocallidea corms were obtained using a 600 MHz 1H-NMR spectrometer. The 1H-NMR analysis led to the identification of choline, succinate, propylene glycol, and lactose, as inhibitory compounds. These four chemical compounds are part of the "Natural Deep Eutectic Solvents" (NADES) that protect plant cells during stress periods, each of which has the potential to inhibit bud growth and development. These compounds are supposedly leached out of the corms during the first rain under natural conditions, possibly accompanied by changes in the ratios of dormancy-breaking phytohormones and inhibitory compounds, to release bud dormancy. The identified chemical compounds heralded a novel frontier in the vegetative propagation of H. hemerocallidea as a medicinal plant, and for its enhanced sustainable uses.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

On the Oxidative Valorization of Lignin to High-Value Chemicals: A Critical Review of Opportunities and Challenges.

The efficient valorization of lignin is crucial if we are to replace current petroleum-based feedstock and establish more sustainable and competitive lignocellulosic biorefineries. Pulp and paper mills and second-generation biorefineries produce large quantities of low-value technical lignin as a by-product, which is often combusted on-site for energy recovery. This Review focuses on the conversion of technical lignins by oxidative depolymerization employing heterogeneous catalysts. It scrutinizes the current literature describing the use of various heterogeneous catalysts in the oxidative depolymerization of lignin and includes a comparison of the methods, catalyst loadings, reaction media, and types of catalyst applied, as well as the reaction products and yields. Furthermore, current techniques for the determination of product yields and product recovery are discussed. Finally, challenges and suggestions for future approaches are outlined.

No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.

BACKGROUND: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany. METHODS: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression). RESULTS: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives. CONCLUSION: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.

Proteomic analysis reveals brain Rab35 as a potential biomarker of mitragynine withdrawal in rats.

Mitragyna speciosa, also known as kratom, has been used for mitigating the severity of opioid withdrawal in humans. Its main indole alkaloid, mitragynine, has been considered as a pharmacotherapy for pain conditions and opioid replacement therapy. However, at high doses, chronic mitragynine may also have an addiction potential. The effects of chronic action of mitragynine in the brain are still unknown. The present study developed a mitragynine withdrawal model in rats and used it for a proteomic analysis of mitragynine withdrawal effects. Mitragynine (30 mg/kg, i.p.) was administered daily over a period of 14 days and then withdrawn. A proteomic analysis revealed that from a total of 1524 proteins identified, 31 proteins were upregulated, and 3 proteins were downregulated in the mitragynine withdrawal model. The Rab35 protein expression increased most profoundly in the mitragynine withdrawal group as compared to vehicle group. Therefore, it is proposed that Rab35 in the brain might be considered as a potential biomarker during mitragynine withdrawal and might be valuable target protein in developing new pharmacotherapies in the future.

The effects of chronic mitragynine (Kratom) exposure on the EEG in rats.

Mitragynine is the main alkaloid isolated from the leaves of Mitragyna speciosa Korth (Kratom). Kratom has been widely used to relieve pain and opioid withdrawal symptoms in humans but may also cause memory deficits. Here we investigated the changes in brain electroencephalogram (EEG) activity after acute and chronic exposure to mitragynine in freely moving rats. Vehicle, morphine (5 mg/kg) or mitragynine (1, 5 and 10 mg/kg) were administered for 28 days, and EEG activity was repeatedly recorded from the frontal cortex, neocortex and hippocampus. Repeated exposure to mitragynine increased delta, but decreased alpha powers in both cortical regions. It further decreased delta power in the hippocampus. These findings suggest that acute and chronic mitragynine can have profound effects on EEG activity, which may underlie effects on behavioral activity and cognition, particularly learning and memory function.

Assessing the Outcome of Holmium Laser Enucleation of the Prostate by Age, Prostate Volume, and a History of Blood Thinning Agents: Report from a Single-Center Series of >1800 Consecutive Cases.

Purpose: To assess perioperative outcomes of holmium laser enucleation of the prostate (HoLEP) in a real-world scenario and with a focus on demanding patient factors, such as large prostate size, advanced patient age, and anticoagulation therapy (AT). Materials and Methods: We retrospectively analyzed HoLEP procedures at our institution between 2010 and 2016. After stratification by prostate volume, age, and AT, perioperative and early voiding characteristics were compared. A multivariable regression model was employed to identify predictors of prolonged time of catheterization (defined as being above group's median). Results: The study cohort consisted of 1816 men with a median age of 71 years (interquartile range [IQR]: 66-76), a median prostate volume of 80 mL (IQR: 58-105), and American Society of Anesthesiologists score ≥3 in 618 men (34%). Median time of enucleation and morcellation was 43 minutes (IQR: 31-60) and 10 minutes (IQR: 6-18), respectively. Perioperative blood transfusions were administered in 44 (2.4%) cases, severe postoperative complications (Clavien-Dindo grade ≥3b) occurred in 61 (3.3%) cases. The median time of catheterization was 2 days (IQR: 2-2), with prolonged catheterization occurring in 277 (15%) cases. After adjustment, large prostates (fourth volume quartile [106-280 mL]) (odds ratio [OR]: 1.8, 95% confidence interval [CI]: 1.3-2.6, p = 0.001), therapeutic low-molecular-weight heparin bridging regimen (OR: 2.2, 95% CI: 1.4-3.6, p = 0.037), low-dose acetylsalicylic acid (OR: 1.5, 95% CI: 1.0-2.2, p = 0.015), and a history of direct oral anticoagulation (OR: 2.3, 95% CI: 1.2-4.0, p = 0.022), but not patient age, were independently associated with prolonged catheterization. Conclusions: We confirm HoLEP as safe and efficient; however, patients with large prostates and patients with a history of AT are at risk of prolonged catheterization.

Cross-reinstatement of mitragynine and morphine place preference in rats.

Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.

The coffee ingredients caffeic acid and caffeic acid phenylethyl ester protect against irinotecan-induced leukopenia and oxidative stress response.

BACKGROUND AND PURPOSE: Irinotecan, used in colorectal cancer therapy, is metabolized by glucuronidation involving different UDP-glucuronosyltransferase (UGT)1A isoforms leading to facilitated elimination from the body. Individuals homozygous for the genetic variants UGT1A1*28 (Gilbert syndrome) and UGT1A7*3 are more susceptible to irinotecan side effects, severe diarrhoea and leukopenia. The aim of this study was to investigate the protective effects and active constituents of coffee during irinotecan therapy using humanized transgenic (htg)UGT1A-WT and htgUGT1A-SNP (carry UGT1A1*28 and UGT1A7*3 polymorphisms) mice. EXPERIMENTAL APPROACH: HtgUGT1A mice were pretreated with coffee or caffeic acid (CA) + caffeic acid phenylethyl ester (CAPE) and injected with irinotecan. The effects of coffee and CA + CAPE were investigated using reporter gene assays, immunoblot, TaqMan-PCR, siRNA analyses and blood counts. KEY RESULTS: Only the combination of the two coffee ingredients, CA and CAPE, mediates protective effects of coffee in a model of irinotecan toxicity by activation of UGT1A genes. Coffee and CA + CAPE significantly increased UGT1A expression and activity along with SN-38 glucuronide excretion in irinotecan-injected htgUGT1A mice, resulting in significant improvement of leukopenia, intestinal oxidative stress and inflammation. CONCLUSION AND IMPLICATIONS: In this study, we identify the compounds responsible for mediating the previously reported coffee-induced activation of UGT1A gene expression. CA and CAPE represent key factors for the protective properties of coffee which are capable of reducing irinotecan toxicity, exerting antioxidant and protective effects. Provided that CA + CAPE do not affect irinotecan efficacy, they might represent a novel strategy for the treatment of irinotecan toxicity.

The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort.

BACKGROUND: Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). OBJECTIVE: To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. METHODS: Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). RESULTS: Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. CONCLUSION: The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.