Robotic Retroperitoneal Versus Transperitoneal Partial Nephrectomy: Outcomes and Learning Curve.

BACKGROUND/AIM: The robotic retroperitoneal approach for renal mass surgery was introduced in 2018 at the Department of Urology in the clinic of Leverkusen, Germany. Clinical criteria for the choice of the access site (trans- vs. retroperitoneal) are not clearly defined. The aim of this study was to explore the learning curve and the impact of the access site on clinical outcome, in order to elucidate which preoperative clinical criteria should be taken into account when choosing the renal approach site. PATIENTS AND METHODS: This retrospective study included 107 patients who underwent robotic tumor surgery between June 2018 and March 2022 at the Department of Urology in the Clinic of Leverkusen, Germany. Data from 86 patients with transperitoneal robotic surgery of the kidney and 21 patients with retroperitoneal access were available for analysis. We evaluated the data of patients in a trans- and a retroperitoneal access group. The preoperative clinical data included anthropomorphic data, the Body Mass Index (BMI) as well as the Preoperative Aspects and Dimensions Used for Anatomical Classification of Renal Masses (PADUA) - score. Intraoperative and postoperative data such as blood loss, clamping time, renal function and the learning curve of the surgeons was used to evaluate the outcomes of the two groups. RESULTS: Operation time in the retroperitoneal group was significantly shorter (p=0.015). Operation-specific variables showed no significant difference between the two groups. PADUA score and hilar clamping time showed no difference (p=0.345 and p=0.130, respectively). The learning curve in the retroperitoneal access group unveiled a noticeable difference in the experience and mastery of the involved surgeons. CONCLUSION: Mastery of the retroperitoneal approach is readily possible for surgeons with previous experience in robotic renal surgery without compromising the operative morbidity. The PADUA-score seems most suitable as a preoperative clinical criterion for choosing the renal approach site.

Primary Staging of Prostate Cancer Patients with [18F]PSMA-1007 PET/CT Compared with [68Ga]Ga-PSMA-11 PET/CT.

BACKGROUND: Hybrid imaging with prostate-specific membrane antigen (PSMA) is gaining importance as an increasingly meaningful tool for prostate cancer (PC) diagnostics and as a guide for therapy decisions. This study aims to investigate and compare the performance of [18F]PSMA-1007 (18F-PSMA) and [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (68Ga-PSMA) in the initial staging of PC patients. METHODS: The data of 88 biopsy-proven patients were retrospectively evaluated. PSMA-avid lesions were compared with the histopathologic Gleason Score (GS) for prostate biopsies, and the results were plotted by receiver operating characteristic (ROC)-curve. Optimal maximum standardized uptake value (SUVmax) cut-off values were rated using the Youden index. RESULTS: 18F-PSMA was able to distinguish GS ≤ 7a from ≥7b with a sensitivity of 62%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 67% for a SUVmax of 8.95, whereas sensitivity was 54%, specificity 91%, PPV 93%, and accuracy 66% for 68Ga-PSMA (SUVmax 8.7). CONCLUSIONS: Both methods demonstrated a high concordance of detected PSMA-avid lesions with histopathologically proven PC. 18F-PSMA and 68Ga-PSMA are both suitable for the characterization of primary PC with a comparable correlation of PSMA-avid lesions with GS. Neither method showed a superior advantage. Our calculated SUVmax thresholds may represent valuable parameters in clinical use to distinguish clinically significant PC (csPC) from non-csPC.

Comparison of [18F]PSMA-1007 with [68Ga]Ga-PSMA-11 PET/CT in Restaging of Prostate Cancer Patients with PSA Relapse.

This study aimed to compare the diagnostic performance of [18F]PSMA-1007 positron emission tomography/computed tomography (PET/CT) (18F-PSMA) and [68Ga]Ga-PSMA-11 PET/CT (68Ga-PSMA) by identifying prostate-specific antigen (PSA) threshold levels for optimal detecting recurrent prostate cancer (PC) and to compare both methods. Retrospectively, the study included 264 patients. The performances of 18F-PSMA and 68Ga-PSMA in relation to the pre-scan PSA were assessed by receiver operating characteristic (ROC) curve. 18F-PSMA showed PC-lesions in 87.5% (112/128 patients), while 68Ga-PSMA identified them in 88.9% (121/136). For 18F-PSMA biochemical recurrent (BCR) patients treated with radical prostatectomy (78/128, patient group: F-RP), a PSA of 1.08 ng/mL was found to be the optimal cut-off level for predicting positive and negative scans (AUC = 0.821; 95%, CI: 0.710−0.932), while for prostatectomized 68Ga-PSMA BCR-patients (89/136, patient group: Ga-RP), the cut-off was 1.84 ng/mL (AUC = 0.588; 95%, CI: 0.410−0.766). In patients with PSA < 1.08 ng/mL (F-RP) 76.3% and <1.84 ng/mL (Ga-RP) 78.6% scans were positive, whereas patients with PSA ≥ 1.08 ng/mL (F-RP) or 1.84 ng/mL (Ga-RP) had positive scan results in 100% and 91.5% (p < 0.001/p = 0.085). The identified PSA thresholds for PSMA-mappable PC lesions in BCR-patients (RP) showed a better separation for 18F-PSMA with regard to the distinguishing of positive and negative PC-lesions compared to 68Ga-PSMA. However, the two PSMA PET/CT tracers gave similar overall findings.

Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α-syn induced by striatal injection of α-syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α-syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α-syn inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that microglia, activated by diffusible, oligomeric α-syn, may play a key role in this process. Our findings uncover new features of α-syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α-syn spreading.

Post-acute delivery of α5-GABAA antagonist, S 44819, improves functional recovery in juvenile rats following stroke.

Hypo-excitability was reported in the peri-infarct tissue following stroke, an effect counteracted by a blockage of α5-GABAA receptors in adult rodents. Our present study aims to evaluate the effect of a selective α5-GABAA receptor antagonist, S 44819, in stroke in juvenile animals. We have set up and characterized an original model of transient ischemic stroke in 28 day-old Sprague-Dawley rats (45-min occlusion of the middle cerebral artery by intraluminal suture). In this model, S 44819 (1, 3 and 10 mg/kg, b.i.d) was orally administered from day 3 to day 16 after stroke onset. Sensorimotor recovery was assessed on day 1, day 9 and day 16 after stroke onset. Results show that rats treated with S 44819 at the doses of 3 and 10 mg/kg displayed a significant improvement of the neurological deficits (neuroscore) on day 9 and day 16, when compared with animals treated with vehicle. Grip-test data analysis reveals that rats treated with S 44819 at the dose of 3 mg/kg displayed a better recovery on day 9 and day 16. These results are in agreement with those previously observed in adult rats, demonstrating that targeting α5-GABAA receptors improves neurological recovery after stroke in juvenile rats.

Teratomatous Elements in Orchiectomy Specimens Are Associated with a Reduced Relapse-Free Survival in Metastasized Testicular Germ Cell Tumors.

INTRODUCTION: The impact of teratomatous elements in orchiectomy specimens of metastasized testicular germ cell tumors (TGCT) regarding oncological outcome is still unclear. METHODS: We performed a retrospective analysis including 146 patients with metastasized TGCT analysing patient characteristics. RESULTS: Twenty-six (18%) of all patients showed teratomatous elements in the orchiectomy specimens. TGCT with teratomatous elements showed a significantly higher frequency of clinical-stage 2C-3 disease (73 vs. 49%, p = 0.031), visceral metastases (58 vs. 32%, p = 0.015), and poor prognosis (p = 0.011) than TGCT without teratomatous elements. Teratoma-containing TGCT revealed a significantly higher rate of post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND, 54 vs. 32%, p = 0.041), with teratomatous elements being more often present in the PC-RPLND specimens (43 vs. 11%, p = 0.020) than nonteratoma-containing primaries. In the Kaplan-Meier estimates, the presence of teratomatous elements in orchiectomy specimens was associated with a significantly reduced relapse-free survival (RFS) (p = 0.049) during a median follow-up of 36 months (10-115.5). CONCLUSIONS: The presence of teratomatous elements in orchiectomy specimens is associated with an advanced tumor stage, worse treatment response as well as a reduced RFS in metastasized TGCT. Consequently, the presence of teratomatous elements might act as a reliable stratification tool for treatment decision in TGCT patients.

Predictors for Outcome and Complications Related to Urinary Diversion.

BACKGROUND/AIM: Predictors for complications such as insufficiency of intestinal anastomosis in urinary diversion and other risk factors are not well defined. We aimed to elucidate predictive factors for complications in urinary diversions based on preoperative comorbidities and major complications. A special focus was set on anastomosis insufficiency as a major complication. PATIENTS AND METHODS: Preoperative comorbidities, postoperative complications, duration of hospital stay, and follow-up were analyzed in 317 patients with urinary diversion. The impact of preoperative comorbidities on diversion types was described and quantified as defined by the age-adjusted Charlson Comorbidity Index. RESULTS: Overall, 14.8% of patients showed anastomosis-related complications, most within the ileal conduit group (15.9% in the cohort). Severe complications (Clavien-Dindo Classification Score >IIIa) were found in smokers (p=0.046), and in patients with vascular diseases (p=0.007), a high American Society of Anaesthesiologists (ASA)-score (p=0.047), a R1- (p=0.009), as well as a pN1 (p=0.007) status. CONCLUSION: Several independent predictors for several postoperative complications in urinary diversions were identified, which were independent of the diversion method.

Deep Learning Based Instance Segmentation of Titanium Dioxide Particles in the Form of Agglomerates in Scanning Electron Microscopy.

The size characterization of particles present in the form of agglomerates in images measured by scanning electron microscopy (SEM) requires a powerful image segmentation tool in order to properly define the boundaries of each particle. In this work, we propose to use an algorithm from the deep statistical learning community, the Mask-RCNN, coupled with transfer learning to overcome the problem of generalization of the commonly used image processing methods such as watershed or active contour. Indeed, the adjustment of the parameters of these algorithms is almost systematically necessary and slows down the automation of the processing chain. The Mask-RCNN is adapted here to the case study and we present results obtained on titanium dioxide samples (non-spherical particles) with a level of performance evaluated by different metrics such as the DICE coefficient, which reaches an average value of 0.95 on the test images.

A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy.

Introduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.

AMG900 as novel inhibitor of the translationally controlled tumor protein.

INTRODUCTION: Cancer is one of the leading causes of death worldwide. Classical cytotoxic chemotherapy exerts high side effects and low tumor selectivity. Translationally controlled tumor protein (TCTP) is a target for differentiation therapy, a promising, new therapeutic approach, which is expected to be more selective and less toxic than cytotoxic chemotherapy. The aim of the present investigation was to identify novel TCTP inhibitors. METHODS: We performed in silico screening and molecular docking using a chemical library of more than 31,000 compounds to identify a novel inhibitor of TCTP. We tested AMG900 in vitro for binding to TCTP by microscale thermophoresis and co-immunoprecipitation. Additionally, we examined the effect of TCTP blockade on cell cycle progression by flow cytometry and Western blotting and cancer cell survival by resazurin assays in MCF-7, SK-OV3 and MOLT-4 cell lines. RESULTS: We identified AMG900 as new inhibitor of TCTP. AMG900 bound to the p53 binding site of TCTP with a free binding energy of -9.63 ±â€¯0.01 kcal/mol. This compound decreased TCTP expression to 23.4 ±â€¯1.59% and increased p53 expression to 194.29 ±â€¯24.27%. Furthermore, AMG900 induced G0/G1 arrest as shown by flow cytometry and Western blot of relevant cell cycle proteins. AMG900 decreased CDK2, CDK4, CDK6, cyclin D1 and cyclin D3 expression, whereas p18, p21 and p27 expression increased. Moreover, AMG900 disturbed TCTP-p53 complexation as shown by co-immunoprecipitation and increased expression of free p53. DISCUSSION: AMG900 may serve as novel lead compound for the development of differentiation therapy approaches against cancer.

Dual-Time Point [68Ga]Ga-PSMA-11 PET/CT Hybrid Imaging for Staging and Restaging of Prostate Cancer.

Routine [68Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [68Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [68Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher (p < 0.001) comparing early and late PET/CT. High positivity rates from routine [68Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast.

Impact of the COVID-19 Pandemic on Urologists in Germany.

BACKGROUND: In order to contain the coronavirus disease 2019 (COVID-19) pandemic, Germany has implemented drastic restrictions on public or social life, while health institutions are invoked to postpone elective procedures. Although urologists are less involved in the direct treatment of COVID-19 patients, the current situation strongly affects the urological work routine. OBJECTIVE: To analyze the impact of the COVID-19 pandemic on various aspects of work and personal life among urologists in Germany. DESIGN, SETTING, AND PARTICIPANTS: A total of 589 urologists in Germany participated in an online survey between March 27 and April 11, 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Participants were stratified into subgroups according to professional characteristics. RESULTS AND LIMITATIONS: Most urologists rated Germany as "well prepared" and the increasing restrictions of social life as "very positive." Routine operation was more restricted in hospitals than in the outpatient sector (p = 0.046). Moreover, urologists from the outpatient sector felt significantly less prepared for the COVID-19 pandemic (p = 0.001), reported a higher shortage of protective medical equipment (p < 0.001), and described a tendency toward a higher level of threat (p = 0.054). Although restrictions regarding telemedicine approaches were reported by 60% of participants, the outpatient sector used telehealth more frequently than hospitals (25.5% vs 17.0%, p < 0.001). Limitations include the national design and the restricted survey period. CONCLUSIONS: This survey systematically evaluates the impact of the COVID-19 pandemic on personal and professional aspects of German urologists. We identified several issues, such as a higher shortage of medical protective equipment in the outpatient sector that could trigger specific measures to further improve the quality of urological care in Germany. PATIENT SUMMARY: We evaluated a potential impact of the coronavirus disease 2019 (COVID-19) pandemic on professional and personal aspects of the urologists in Germany. Our results suggest that the outpatient sector should receive specific attention as, for example, shortage of protective equipment was more common.

PSA and PSA Kinetics Thresholds for the Presence of 68Ga-PSMA-11 PET/CT-Detectable Lesions in Patients With Biochemical Recurrent Prostate Cancer.

68Ga-PSMA-11 positron-emission tomography/computed tomography (PET/CT) is commonly used for restaging recurrent prostate cancer (PC) in European clinical practice. The goal of this study is to determine the optimum time for performing these PET/CT scans in a large cohort of patients by identifying the prostate-specific-antigen (PSA) and PSA kinetics thresholds for detecting and localizing recurrent PC. This retrospective analysis includes 581 patients with biochemical recurrence (BC) by definition. The performance of 68Ga-PSMA-11 PET/CT in relation to the PSA value at the scan time as well as PSA kinetics was assessed by the receiver-operating-characteristic-curve (ROC) generated by plotting sensitivity versus 1-specificity. Malignant prostatic lesions were identified in 77%. For patients that were treated with radical prostatectomy (RP) a PSA value of 1.24 ng/mL was found to be the optimal cutoff level for predicting positive and negative scans, while for patients previously treated with radiotherapy (RT) it was 5.75 ng/mL. In RP-patients with PSA value <1.24 ng/mL, 52% scans were positive, whereas patients with PSA ≥1.24 ng/mL had positive scan results in 87%. RT-patients with PSA <5.75 ng/mL had positive scans in 86% and and for those with PSA ≥5.75 ng/mL 94% had positive scans. This study identifies the PSA and PSA kinetics threshold levels for the presence of 68Ga-PSMA-11 PET/CT-detectable PC-lesions in BC patients.

Effect of glucose and insulin supplementation on the isolation of primary human hepatocytes.

Primary human hepatocytes (PHHs) remain the gold standard for in vitro investigations of xenobiotic metabolism and hepatotoxicity. However, scarcity of liver tissue and novel developments in liver surgery has limited the availability and quality of tissue samples. In particular, warm ischemia shifts the intracellular metabolism from aerobic to anaerobic conditions, which increases glycogenolysis, glucose depletion and energy deficiency. Therefore, the aim of the present study was to investigate whether supplementation with glucose and insulin during PHH isolation could reconstitute intracellular glycogen storage and beneficially affect viability and functionality. Furthermore, the study elucidated whether the susceptibility of the tissue's energy status correlates with body mass index (BMI). PHHs from 12 donors were isolated from human liver tissue obtained from partial liver resections using a two-step EDTA/collagenase perfusion technique. For a direct comparison of the influence of glucose/insulin supplementation, we modified the setup, enabling the parallel isolation of two pieces of one tissue sample with varying perfusate. Independent of the BMI of the patient, the glycogen content in liver tissue was notably low in the majority of samples. Furthermore, supplementation with glucose and insulin had no beneficial effect on the glycogen concentration of isolated PHHs. However, an indirect improvement of the availability of energy was shown by increased viability, plating efficiency and partial cellular activity after supplementation. The plating efficiency showed a striking inverse correlation with increasing lipid content of PHHs. However, 60 h of cultivation time revealed no significant impact on the maintenance of albumin and urea synthesis or xenobiotic metabolism after supplementation. In conclusion, surgical procedures and tissue handling may decrease hepatic energy resources and lead to cell stress and death. Consequently, PHHs with low energy resources die during the isolation process without supplementation of glucose/insulin or early cell culture, while their survival rates are improved with glucose/insulin supplementation.

Radiation Dose in Prostatic Artery Embolization Using Cone-Beam CT and 3D Roadmap Software.

PURPOSE: To evaluate the radiation dose in patients undergoing prostatic artery embolization (PAE) using cone-beam CT and 3-dimensional (3D) guidance software. MATERIALS AND METHODS: In this single-center retrospective study, 100 patients with benign prostatic hyperplasia (mean prostate volume, 83.6 mL ± 44.2; 69.4 ± 9.6 years of age; body mass index, 26.5 ± 4.2) were treated using PAE between October 2016 and April 2018. Informed consent was obtained from all participants included in the study. All patients received at least 1 intraprocedural cone-beam CT per side for evaluation of the vessel anatomy and software rendering of 3D guidance for catheter guidance. Digital subtraction angiography (DSA) was performed in the distal branches only. The total dose area product (DAP), along with the DAP attributed to fluoroscopy, DSA, and cone-beam CT, were assessed. RESULTS: Bilateral embolization was achieved in 83 patients (83%). The average total DAP was 134.4 Gy ⋅ cm2 ± 69.5 (range, 44.7-410.9 Gy ⋅ cm2). Fluoroscopy, DSA, and cone-beam CT accounted for 35.5 Gy ⋅ cm2 ± 21.3 (range, 8.6-148.6 Gy ⋅ cm2) or 26.4% (percentage of total DAP), 58.2 Gy ⋅ cm2 ± 48.3 (range, 10.3-309.3 Gy ⋅ cm2) or 43.3%, and 40.7 Gy ⋅ cm2 ± 14.5 (range, 15.9-86.3 Gy ⋅ cm2) or 30.3%, respectively. Average procedure time was 89.4 ± 27.0 minutes, and the average fluoroscopy time was 30.9 ± 12.2 minutes. CONCLUSIONS: Intraprocedural cone-beam CT in combination with 3D guidance software allows for identification and catheterization of the prostatic artery in PAE. Furthermore, the results of this trial indicate that this study protocol may lead to a low overall radiation dose.

Biopiracy versus One-World Medicine-From colonial relicts to global collaborative concepts.

BACKGROUND: Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism. HYPOTHESIS: The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe. STUDY DESIGN: Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communities. The European community adopted the Nagoya protocol, and the corresponding regulations will be implemented into national legislation among the member states. Despite pleasing progress, infrastructural problems of the health care systems in developing countries still remain. Current approaches to secure primary health care offer only fragmentary solutions at best. Conventional medicine from industrialized countries cannot be afforded by the impoverished population in the Third World. Confronted with exploding costs, even health systems in Western countries are endangered to burst. Complementary and alternative medicine (CAM) is popular among the general public in industrialized countries, although the efficacy is not sufficiently proven according to the standards of evidence-based medicine. CAM is often available without prescription as over-the-counter products with non-calculated risks concerning erroneous self-medication and safety/toxicity issues. The concept of integrative medicine attempts to combine holistic CAM approaches with evidence-based principles of conventional medicine. CONCLUSION: To realize the concept of One-World Medicine, a number of standards have to be set to assure safety, efficacy and applicability of traditional medicine, e.g. sustainable production and quality control of herbal products, performance of placebo-controlled, double-blind, randomized clinical trials, phytovigilance, as well as education of health professionals and patients.

Prevention from radiation damage by natural products.

BACKGROUND: Radiotherapy is a mainstay of cancer treatment since decades. Ionizing radiation (IR) is used for destruction of cancer cells and shrinkage of tumors. However, the increase of radioresistance in cancer cells and radiation toxicity to normal tissues are severe concerns. The exposure to radiation generates intracellular reactive oxygen species (ROS), which leads to DNA damage by lipid peroxidation, removal of thiol groups from cellular and membrane proteins, strand breaks and base alterations. HYPOTHESIS: Plants have to deal with radiation-induced damage (UV-light of sun, other natural radiation sources). Therefore, it is worth speculating that radioprotective mechanisms have evolved during evolution of life. We hypothesize that natural products from plants may also protect from radiation damage caused as adverse side effects of cancer radiotherapy. METHODS: The basis of this systematic review, we searched the relevant literature in the PubMed database. RESULTS: Flavonoids, such as genistein, epigallocatechin-3-gallate, epicatechin, apigenin and silibinin mainly act as antioxidant, free radical scavenging and anti-inflammatory compounds, thus, providing cytoprotection in addition to downregulation of several pro-inflammatory cytokines. Comparable effects have been found in phenylpropanoids, especially caffeic acid phenylethylester, curcumin, thymol and zingerone. Besides, resveratrol and quercetin are the most important cytoprotective polyphenols. Their radioprotective effects are mediated by a wide range of mechanisms mainly leading to direct or indirect reduction of cellular stress. Ascorbic acid is broadly used as antioxidant, but it has also shown activity in reducing cellular damage after irradiation mainly due to its antioxidant capabilities. The metal ion chelator, gallic acid, represents another natural product attenuating cellular damage caused by radiation. CONCLUSIONS: Some secondary metabolites from plants reveal radioprotective features against cellular damage caused by irradiation. These results warrant further analysis to develop phytochemicals as radioprotectors for clinical use.

Replicability of Physical Exercise Interventions in Lung Transplant Recipients; A Systematic Review.

Introduction: This systematic review aimed to assess the replicability of physical exercise interventions in lung transplantation patients. For replicability we focused on (1) the description of training principles, (2) the description of FITT components and adherence to the interventions, (3) the amount of detailed information given on the physical exercise intervention, and (4) reporting the methodological quality of the included works. Methods: Relevant databases (Medline-Ovid, EMBASE, CINAHL, PsychInfo, Cochrane Library) were searched. Author dyads selected and systematically analyzed the included studies independent from each other. A purpose developed checklist was used to assess the details of the exercise interventions and their methodological quality. Results: From the seven included manuscripts, three described resistance training, one endurance, and three combined training approaches. All manuscripts reported specificity and initial values, six manuscripts mention progression and overload. The exercise principle reversibility was reported once and diminishing returns was not reported at all. All studies reported the type of exercise, three studies reported intensity and one study reported time for training. Not any study completely reported frequency or described adherence to the intervention. Lack of detailed reporting was identified as the cause for murky description of the interventions. The highest score for intervention description was 5 of possible 12 items. Conclusions: Replicability of many exercise interventions in LTX is not warranted due too poor descriptions of important items related to training. In particular there were insufficiently detailed reporting of training principles and FITT components in programs developed for LTX. Future interventions that aim to train LTX patients should spent effort in writing reports in which the intervention is detailed to such an extent that full replicability in clinical settings can be guaranteed.

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy. Mol Cancer Ther; 17(8); 1739-51. ©2018 AACR.