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Abstract Over the past three decades, there has been increasing interest in miniaturized percutaneous nephrolithotomy (mPCNL) techniques featuring smaller tracts as they offer potential solutions to mitigate complications associated with standard PCNL (sPCNL). However, despite this growing acceptance and recognition of its benefits, unresolved controversies and acknowledged limitations continue to impede widespread adoption due to a lack of consensus on optimal perioperative management strategies and procedural tips and tricks. In response to these challenges, an international panel comprising experts from the International Alliance of Urolithiasis (IAU) took on the task of compiling an expert consensus document on mPCNL procedures aimed at providing urologists with a comprehensive clinical framework for practice. This endeavor involved conducting a systematic literature review to identify research gaps (RGs), which formed the foundation for developing a structured questionnaire survey. Subsequently, a two-round modified Delphi survey was implemented, culminating in a group meeting to generate final evidence-based comments. All 64 experts completed the second-round survey, resulting in a response rate of 100.0%. Fifty-eight key questions were raised focusing on mPCNLs within 4 main domains, including general information (13 questions), preoperative work-up (13 questions), procedural tips and tricks (19 questions), and postoperative evaluation and follow-up (13 questions). Additionally, 9 questions evaluated the experts’ experience with PCNLs. Consensus was reached on 30 questions after the second-round survey, while professional statements for the remaining 28 key questions were provided after discussion in an online panel meeting. mPCNL, characterized by a tract smaller than 18 Fr and an innovative lithotripsy technique, has firmly established itself as a viable and effective approach for managing upper urinary tract stones in both adults and pediatrics. It offers several advantages over sPCNL including reduced bleeding, fewer requirements for nephrostomy tubes, decreased pain, and shorter hospital stays. The series of detailed techniques presented here serve as a comprehensive guide for urologists, aiming to improve their procedural understanding and optimize patient outcomes.

Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0–36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Objective: To evaluate the efficacy and safety of 2 doses of vilaprisan vs. placebo in participants with symptomatic endometriosis. Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b trial (NCT03573336). The initially planned sample size was 315 patients. Recruitment was paused to assess long-term toxicity findings in rodents; although the findings were assessed as likely to be of limited clinical relevance in humans, the study was closed by the sponsor. During the pause, enrolled patients completed 3 or 6 months of treatment per their assigned regimen. Setting: University hospitals, a regional hospital, and a private clinic. Patients: Premenopausal adults with confirmed endometriosis and moderate-to-severe pelvic pain (≥4/10 on a numerical rating scale) were enrolled. Inclusion required protocol adherence, including ≥24 diary entries, and an average pain score of ≥3.5. Intervention: Participants were randomly assigned 1:1:1 to receive vilaprisan (2 mg), vilaprisan (4 mg), or placebo. Main Outcome Measures: The primary outcome was a change in the 7-day mean “worst pain” (per the endometriosis symptom diary item 1) from baseline to month 3. All analyses were descriptive only. Results: Eight participants were randomly assigned to treatment before the study pause: 6 received vilaprisan (4 mg, n = 4 and 2 mg, n = 2), and 2 received placebo. The 6 vilaprisan recipients experienced an improvement in endometriosis-associated pelvic pain, whereas the 2 placebo recipients experienced no change or increased pain; all 8 participants had decreased use of pain medication. Bleeding intensity decreased from baseline in the vilaprisan group. Conclusion: The study findings suggest that vilaprisan may improve outcomes in patients with endometriosis. Further studies in larger populations would be needed to accurately assess treatment effects. Clinical Trial Registration Number: NCT03573336

Introduction. The emergence of new scientific and clinical evidence on the use of retrograde intrarenal surgery (RIRS) for the management of kidney stones has prompted periodic systematisation, analysis, and evaluation of outcomes to standardise its application and determine future directions for research and development.Objective. To present the Russian adaptation of a guideline on retrograde intrarenal surgery from the International Urolithiasis Alliance guideline series to provide a theoretical basis for urologists performing RIRS.Materials & Methods. A systematic review was conducted on the RIRS-associated publications available in the PubMed database to prepare a set of recommendations during the period from 1 January 1964 until 1 October 2021. The recommendations were evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system, which classifies, evaluates, develops, and examines recommendations. The modified Oxford Centre for Evidence-Based Medicine's (OCEBM) system for categorising the level of evidence and relevant comments have been applied to assess the strength of the conclusions.Results. The research team conducted a comprehensive analysis of 36 published clinical guidelines on the following topics: 1. Indications and Contraindications 2. Preoperative Imaging 3. Preoperative Ureteral Stenting 4. Preoperative Medications 5. Perioperative Use of Antibiotics 6. Use of Antithrombotic Therapy 7. Anesthesia Issues 8. Intraoperative Positioning 9. Equipment 10. Complications.Conclusion. A series of recommendations for RIRS, offered here should help provide safe and effective performance of RIRS.

Objective: To provide a comprehensive review on the existing literature on medical management of urolithiasis. Methods: A thorough literature review was performed using Medline, PubMed/PMC, Embase, and the Cochrane Database of Systematic Reviews up to December 2022 to identify publications on the medical management of urolithiasis. Studies that assessed dietary and pharmacologic management of urolithiasis were reviewed; studies on medical expulsive therapy were not included in this review. Results: Medical management of urolithiasis ranges from the prophylactic management of kidney stone disease to dissolution therapies. While most treatment concepts have been long established, large randomized controlled trials are scarce. Dietary modification and increased fluid intake remain cornerstones in the conservative management of urolithiasis. A major limitation for medical management of urolithiasis is poor patient compliance. Conclusion: Medical management of urolithiasis is more important in patients with recurrent urolithiasis and patients with metabolic abnormalities putting them at higher risk of developing stones. Although medical management can be effective in limiting stone recurrence, medical interventions often fail due to poor compliance.

Abstract The transition from inorganic catalysis through minerals to organic catalysis by enzymes is a necessary step in the emergence of life. Our work is elucidating likely reactions at the earliest moments of Life, prior to the existence of enzymatic catalysis, by exploring essential intersections between nickel bioinorganic chemistry and pterin biochemistry. We used a prebiotically-inspired acetylene-containing volcanic hydrothermal experimental environment to shed light on the efficient formation of nickel-organo complexes. The simplest bis(dithiolene)nickel complex (C2H2S2)2Ni was identified by UV/Vis spectroscopy, mass spectrometry, nuclear magnetic resonance. Its temporal progression and possible function in this simulated early Earth atmosphere were investigated by isolating the main bis(dithiolene)nickel species from the primordial experimental setup. Using this approach, we uncovered a significant diversity of nickel-organo compositions by identifying 156 elemental annotations. The formation of acetaldehyde through the subsequent degradation of these organo-metal complexes is intriguing, as it is reminiscent of the ability of Pelobacter acetylenicus to hydrate acetylene to acetaldehyde via its bis(dithiolene)-containing enzyme acetylene hydratase. As our findings mechanistically characterize the role of nickel sulfide in catalyzing the formation of acetaldehyde, this fundamental pre-metabolic reaction could play the role of a primitive enzyme precursor of the enzymatic acetylene metabolism and further strengthen the role of acetylene in the molecular origin of life.

Abstract Chemical complexity is vital not only for the origin of life but also for biological evolution. The chemical evolution of a complex prebiotic mixture containing acetylene, carbon monoxide (CO), and nickel sulfide (NiS) has been analyzed with mass spectrometry as an untargeted approach to reaction monitoring. Here we show through isotopic 13C-labelling, multiple reaction products, encompassing diverse CHO and CHOS compounds within the complex reaction mixture. Molecules within the same chemical spaces displayed varying degrees of 13C-labelling, enabling more robust functional group characterization based on targeted investigations and differences in saturation levels among the described classes. A characteristic C2-addition pattern was detected in all compound classes in conjunction with a high diversity of thio acids, reminiscent of extant microbial C2-metabolism. The analysis involved a time-resolved molecular network, which unveiled the behavior of sulfur in the system. At the onset of the reaction, early formed compounds contain more sulfur atoms compared to later emerging compounds. These results give an essential insight into the still elusive role of sulfur dynamics in the origin of life. Moreover, our results provide temporally resolved evidence of the progressively increasing molecular complexity arising from a limited number of compounds.

Abstract Microscopic compartmentalization is beneficial in synthetic chemistry and indispensable for the evolution of life to separate a reactive “inside” from a hydrolyzing “outside”. Here, we show compartmentalization in aqueous solution containing mixtures of fatty acids up to 19 carbon atoms which were synthesized by one-pot reactions of acetylene and carbon monoxide in contact with nickel sulfide at 105 °C, reaction requirements which are compatible to Hadean Early Earth conditions. Based on confocal, dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements, vesicle-like structures with diameters of 10–150 nm are formed after solvent extraction and resolubilisation. Moreover fluorescent dye was encapsulated into the structures proving their vesicular properties. This self-assembly could also have occurred on Early Earth as a crucial step in establishing simple membranes of proto-cells as a prerequisite in the evolution of metabolism and life.

Amino acids are one of the most important building blocks of life. During the biochemical process of translation, cells sequentially connect amino acids via amide bonds to synthesize proteins, using the genetic information in messenger RNA (mRNA) as a template. From a prebiotic perspective (i.e., without enzymatic catalysis), joining amino acids to peptides via amide bonds is difficult due to the highly endergonic nature of the condensation reaction. We show here that amides can be formed in reactions catalyzed by the transition metal sulfides from acetylene, carbon monoxide and ammonia under aqueous conditions. Some α- and β-amino acids were also formed under the same conditions, demonstrating an alternative cyanide-free path for the formation of amino acids in prebiotic environments. Experiments performed with stable isotope labeled precursors, like 15NH4Cl and 13C-acetylene, enabled the accurate mass spectroscopic identification of the products formed from the starting materials and their composition. Reactions catalyzed using the transition metal sulfides seem to offer a promising alternative pathway for the formation of amides and amino acids in prebiotic environments, bypassing the challenges posed by the highly endergonic condensation reaction. These findings shed light on the potential mechanisms by which the building blocks of life could have originated on early Earth.

Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. Funding: Found in Acknowledgement.

Aldehydes can be formed under extraterrestrial conditions, however, the synthesis of aldehydes on early Earth remains largely unclear. Here, the authors report the formation of acetaldehydes and higher condensation products starting from a gaseous mixture of acetylene and carbon monoxide over nickel sulfide containing water with various pH-values under hydrothermal conditions.

Objective The substitution of an in-study control population with a historical control (HC) population is considered a viable option for reducing the necessary recruitment of control patients. However, it is necessary to evaluate whether this method is applicable to studies on indications targeting endometriosis-associated pelvic pain (EAPP). This study aims to evaluate the potential bias in the results of an EAPP study with an HC arm.Methods For this case study, we re-evaluated data from a randomised, placebo-controlled trial using dienogest daily to treat EAPP with an HC arm based on data from a second randomised, placebo-controlled trial in the same indication. Propensity Score (PS) matching was used to match between the treatment and HC arm on all baseline variables. To evaluate the effect of matching on the introduced bias, we evaluated efficacy parameters with the full treatment and control group, as well as the matched group.Results The difference between means (placebo minus treatment) in change in pain, as measured on the Visual Analogue Scale from baseline to end of treatment, deviates in the comparison treatment/pool of HC (7.15 (0.22 to 14.08)) from the overall in-study group (reference: 11.89 (6.06 to 17.73)). After PS matching on the baseline variables, the difference between means (11.79 (4.09 to 19.5)) is close to the reference.Conclusions Using HC with PS matching has proven to be useful in the setting of treating EAPP, while emphasis must be given to the selection mechanism and the underlying assumptions. This case study has shown that even for studies which are very similar in design, heterogeneity and between-study variations are present. With the use of an HC arm, it was possible to reproduce similar results than in the original study, while the PS matching improved the comparability considerably. For the main endpoint, PS matching could reproduce the original study results.Trial registration number NCT00225199, NCT00185341

Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P

BackgroundPrognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well.MethodsPatients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/β+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival.ResultsWe identified 15 patients with primary disseminated disease and 14 with metastatic relapse who were transplanted from a haploidentical donor to improve prognosis. Three-year event-free survival (EFS) was 18,1% and predominantly determined by disease relapse. Survival depended on response to pre-transplant therapy (3y-EFS of patients in complete or very good partial response: 36,4%). However, no patient with metastatic relapse could be rescued.ConclusionHaplo-HSCT for consolidation after conventional therapy seems to be of interest for some, but not for the majority of patients with high-risk pediatric sarcomas. Evaluation of its future use as basis for subsequent humoral or cellular immunotherapies is necessary.

The definition of biomarkers to predict therapy responses to immune-checkpoint inhibitors represent an unmet clinical need. Here the authors provide evidences that platelet-derived PD-L1 could serve as a prognostic and predictive biomarker in patients with non-small cell lung cancer.

Abstract Background The Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS) are patient-reported outcome measures developed to evaluate efficacy in clinical trials and clinical practice. The ESD is a daily electronic diary assessing symptom severity; the EIS is a weekly electronic diary assessing symptom impact. This study explored the importance of symptoms (ESD items) and impacts (EIS domains), perspectives on scoring algorithms, and clinically important difference (CID) thresholds to inform clinical trial score interpretation. Methods Endometriosis patients in Germany (n = 8) and the US (n = 17), and expert clinicians (n = 4) in Germany, the US, Spain, and Finland participated in semi-structured qualitative interviews comprising structured tasks. Interview transcripts were analyzed using thematic analysis techniques. Results Quality and severity of endometriosis-associated pelvic pain varied considerably among patients; some experienced pelvic pain daily, others during menstrual bleeding (dysmenorrhea) only. Patients and clinicians ranked “worst pelvic pain” as the most meaningful pain concept assessed by the ESD, followed by constant and short-term pelvic pain. Preferences for summarizing daily pain scores over the 28-day menstrual cycle depended on individuals’ experience of pain: patients experiencing pain daily preferred scores summarizing data for all 28 days; patients primarily experiencing pain during selected days, and their treating clinicians preferred scores based on the most severe pain days. Initial CID exploration for the “worst pelvic pain” 0–10 numerical rating scale (0–10 NRS) revealed that, for most patients, a 2- or 3-point reduction was considered meaningful, depending on baseline severity. Patients and clinicians ranked “emotional well-being” and “limitations in physical activities” as the most important EIS domains. Conclusions This study informs the use of the ESD and EIS as clinically relevant measures of endometriosis symptoms and their impact. Findings from the ESD highlight the importance of individual-patient assessment of pain experience and identify “worst pelvic pain” as the most meaningful symptom assessed. Aggregating scores over the 28-day menstrual cycle may inform meaningful endpoints for clinical trials. Diverse EIS concepts (e.g. impact on emotional well-being and physical activities) are meaningful to patients and clinicians, emphasizing the importance of evaluating the impact on both to comprehensively assess treatment efficacy and decisions. Trial registration Not applicable. Qualitative, non-interventional study; registration not required.

Abstract Background To evaluate the psychometric and measurement properties of two patient-reported outcome instruments, the menstrual pictogram superabsorbent polymer-containing version 3 (MP SAP-c v3) and Uterine Fibroid Daily Bleeding Diary (UF-DBD). Test-retest reliability, criterion, construct validity, responsiveness, missingness and comparability of the MP SAP-c v3 and UF-DBD versus the alkaline hematin (AH) method and a patient global impression of severity (PGI-S) were analyzed in post hoc trial analyses. Results Analyses were based on data from up to 756 patients. The full range of MP SAP-c v3 and UF-DBD response options were used, with score distributions reflecting the cyclic character of the disease. Test-retest reliability of MP SAP-c v3 and UF-DBD scores was supported by acceptable intraclass correlation coefficients when stability was defined by the AH method and Patient Global Impression of Severity (PGI-S) scores (0.80–0.96 and 0.42–0.94, respectively). MP SAP-c v3 and UF-DBD scores demonstrated strong and moderate-to-strong correlations with menstrual blood loss assessed by the AH method. Scores increased in monotonic fashion, with greater disease severities, defined by the AH method and PGI-S scores; differences between groups were mostly statistically significant (P

Abstract Background Pictorial blood loss assessment charts (PBACs) represent the most widely used method to assess menstrual blood loss (MBL) in clinical trials. The aims of this review were to: (1) determine the diagnostic accuracy of PBACs that have been validated against the reference alkaline hematin technique; (2) categorize the pitfalls of using obsolete and nonvalidated charts; (3) provide guidelines for development of a new PBAC or use of an existing chart to measure MBL in clinical trials; and (4) consider the feasibility of using pictorial charts in primary care. Methods A literature review was conducted using Embase and MEDLINE databases. The review identified reports of women with self-perceived or actual heavy menstrual bleeding (HMB), bleeding disorders, abnormal uterine bleeding, leiomyomata (uterine fibroids) or endometriosis, and women undergoing treatment for HMB, as well as those with normal menstrual periods. Data were reviewed from studies that focused on the development and validation of PBACs and from those that used derivative noncertified charts to assess HMB. Results Nine studies reported validation of PBAC scoring systems against the alkaline hematin technique. Across these studies, the sensitivity was 58–97%, the specificity was 7.5–95.5%, the positive and negative likelihood ratios were 1.1–13.8 and 0.14–0.56, respectively, and the diagnostic odds ratio was 2.6–52.4. The cut-off score above which the diagnosis of HMB was made ranged from 50 to 185. Several modifications of these PBACs were used in other studies; however, objective confirmation of their validity was not reported. Overall, there was widespread inconsistency of chart design, scoring systems, diagnostic cut-off limits and post-treatment outcome measures. Conclusions PBACs are best suited to the controlled and specific environment of clinical studies, where clinical outcome parameters are defined. The current lack of standardization precludes widespread use of the PBAC in primary care. Review registration number PROSPERO international prospective register of systematic reviews: CRD42016030083.

Abstract Background Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS). Methods The ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France (n = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany (n = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process. Results Pelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., ‘pelvis’ vs. ‘abdomen’). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified. Conclusions Evidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women’s lives. Future research will seek to establish the measurement properties of the measures.

Cytochrome bd-type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since bd oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing bd oxidases include the Mycobacterium tuberculosis (Mtb) bacterium that causes tuberculosis (TB) in humans, the Vibrio cholerae bacterium that causes cholera, the Pseudomonas aeruginosa bacterium that contributes to antibiotic resistance and sepsis, and the Campylobacter jejuni bacterium that causes food poisoning. Escherichia coli (E. coli) is another organism exhibiting the cytochrome bd oxidase. Since it has the highest sequence identity to Mtb (36%) and we are ultimately interested in finding drug targets for TB, we have built parameters for the E. coli bd oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome bd-type oxidases (heme b558, heme b595, and heme d) along with their axial ligands. This data report includes the parameter and library files that can be used with Amber’s LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions.

Acute myeloid leukemia (AML) and B-cell acute lymphocytic leukemia (B-ALL) are severe blood malignancies affecting both adults and children. Chimeric antigen receptor (CAR)-based immunotherapies have proven highly efficacious in the treatment of leukemia. However, the challenge of the immune escape of cancer cells remains. The development of more affordable and ready-to-use therapies is essential in view of the costly and time-consuming preparation of primary cell-based treatments. In order to promote the antitumor function against AML and B-ALL, we transduced NK-92 cells with CD276-CAR or CD19-CAR constructs. We also attempted to enhance cytotoxicity by a gene knockout of three different inhibitory checkpoints in NK cell function (CBLB, NKG2A, TIGIT) with CRISPR-Cas9 technology. The antileukemic activity of the generated cell lines was tested with calcein and luciferase-based cytotoxicity assays in various leukemia cell lines. Both CAR-NK-92 exhibited targeted cytotoxicity and a significant boost in antileukemic function in comparison to parental NK-92. CRISPR-Cas9 knock-outs did not improve B-ALL cytotoxicity. However, triple knock-out CD276-CAR-NK-92 cells, as well as CBLB or TIGIT knock-out NK-92 cells, showed significantly enhanced cytotoxicity against U-937 or U-937 CD19/tag AML cell lines. These results indicate that the CD19-CAR and CD276-CAR-NK-92 cell lines’ cytotoxic performance is suitable for leukemia killing, making them promising off-the-shelf therapeutic candidates. The knock-out of CBLB and TIGIT in NK-92 and CD276-CAR-NK-92 should be further investigated for the treatment of AML.

Despite the recent success of CAR T cells targeting CD19 and CD22 in hematological malignancies, the production of CAR T cells still requires an extensive manufacturing process. The well-established NK-92 cell line provides a promising alternative to produce CAR-modified effector cells in a GMP-compliant, cost-effective way. NK-92 can be redirected against a variety of surface antigens by our adapter CAR (AdCAR) system utilizing biotinylated antibodies (bAb) as adapter molecules. Selected bAb were capable of inducing significant AdCAR NK-92-mediated lysis of non-Hodgkin lymphoma (NHL) and mantle-cell lymphoma (MCL) cell lines as well as primary MCL and chronic lymphocytic leukemia (CLL) cells. AdCAR specificity was proven using a JeKo-1 CD19/CD20 knockout antigen-loss model. Moreover, through combinations of bAb, AdCAR NK-92 cells are capable of combatting tumor antigen evasion mechanisms. In conclusion, we successfully generated the AdCAR NK-92 cell line which can be manufactured as an “off-the-shelf, on-demand” product allowing universal and tunable tumor targeting.

Abstract Background Since the publication over 50 years ago of the alkaline hematin method for quantifying menstrual blood loss (MBL) many new approaches have been developed to assess MBL. The aim of this systematic review is to determine for methods of measuring MBL: ability to distinguish between normal and heavy menstrual bleeding (HMB); practicalities and limitations in the research setting; and suitability for diagnosing HMB in routine clinical practice. Methods Embase®™, MEDLINE®, and ClinicalTrials.gov were screened for studies on the development/validation of MBL assessment methods in women with self-perceived HMB, actual HMB or uterine fibroids, or patients undergoing treatment for HMB. Studies using simulated menstrual fluid and those that included women with normal MBL as controls were also eligible for inclusion. Extracted data included study population, results of validation, and advantages/disadvantages of the technique. Results Seventy-one studies fulfilled the inclusion criteria. The sensitivity and/or specificity of diagnosing HMB were calculated in 16 studies of methods involving self-perception of MBL (11 pictorial), and in one analysis of the menstrual-fluid-loss (MFL) method; in 13 of these studies the comparator was the gold standard alkaline hematin technique. Sensitivity and specificity values by method were, respectively: MFL model, 89, 98%; pictorial blood loss assessment chart (PBAC), 58–99%, 7.5–89%; menstrual pictogram, 82–96%, 88–94%; models/questionnaires, 59–87%, 62–86%, and complaint of HMB, 74, 74%. The power of methods to identify HMB was also assessed using other analyses such as comparison of average measurements: statistical significance was reported for the PBAC, MFL, subjective complaint, and six questionnaires. In addition, PBAC scores, menstrual pictogram volumes, MFL, pad/tampon count, iron loss, and output from three questionnaires correlated significantly with values from a reference method in at least one study. In general, pictorial methods have been more comprehensively validated than questionnaires and models. Conclusions Every method to assess MBL has limitations. Pictorial methods strike a good balance between ease of use and validated accuracy of MBL determination, and could complement assessment of HMB using quality of life (QoL) in the clinical and research setting. Trial registration PRISMA registration number: CRD42016032956.

Abstract Background Endometriosis is a common, chronic condition in women of reproductive age that is characterized by the presence of functional endometriotic lesions outside the uterus. The Endometriosis Symptom Diary (ESD) is an electronic patient-reported outcome (ePRO) instrument that assesses women’s experience of endometriosis symptoms, with pain scored using a 0–10 numeric rating scale. This study investigated patterns of data missing from the ESD in the VALEPRO study. Methods Post hoc analyses of missing data were conducted. Results Of 272 participants using the ESD, 26.5% had no missing diary entries, 46.7% had > 0–5% of entries missing, 13.2% had > 5–10% of entries missing and 13.6% had > 10% of entries missing over the entire study period. The duration of missing episodes (defined as ≥1 consecutive days with missing diary entries) was generally short; most (81.4%) were 1 day. The difference in mean worst pain scores between missing and complete episodes per participant was − 0.1, suggesting that missing episodes were not related to severity of pain. Entries were significantly more likely to be missing on Fridays (18.5%) and Saturdays (22.9%) compared with other days of the week (p

Porphyrins, corrins, and tetrapyrroles constitute macrocycles in essential biomolecules such as heme, chlorophyll, cobalamin, and cofactor F430. The chemical synthesis as well as the enzymatic synthesis of these macrocycles starts from pyrrole derivatives. We here show that pyrrole and dimethyl pyrrole can be formed under the simulated volcanic, hydrothermal conditions of Early Earth, starting from acetylene, propyne, and ammonium salts in the presence of NiS or CoS as catalysts.

The paper focuses on the German food retailing industry with its market characteristics and the status quo of online food retailing in Germany by analysing data from market research institutes and consumer direct questionnaire. The paper examines the consumers’ perceptions of online as well as offline grocery shopping. As a result, an online grocery model was created using PLS-SEM modelling. It illustrates all major success factors related to the consumer’s willingness to shop for groceries online in Germany. The main factors influencing the willingness to shop for groceries online are awareness of benefits, need for more convenience, and change of the lack of trust in the new distribution channel. We identified some consumer groups that are more open to online shopping as they benefit more from online grocery shopping. Especially working mothers and young professionals are the consumer groups with a high potential interest.

PURPOSE: To evaluate the clinical outcome after placement of AdVance® sling in men with stress urinary incontinence after prostate surgery. MATERIALS AND METHODS: Incontinence was assessed on basis of number of pad usage. Patients' satisfaction was evaluated using a non-validated patient questionnaire at 12 months post-operatively. RESULTS: Incontinence cure rate (no pad usage) was 61.5% (16/26) and improvement (1-2 pads per day) was seen in 26.9% (7/26). No improvement was observed in 11.5% (3/26) of patients. A total of 87.5% (21/24) of patients were very satisfied with the operation 22 months after surgery. Success rate in patients with prior radiation therapy (20% cure; 40% improvement) was significantly worse. CONCLUSIONS: Placement of the AdVance® sling represents an effective and safe treatment option for patients with post prostate surgery incontinence. Patients that underwent radiotherapy after prostate surgery had lower success rate.

In the last 4 years many studies have been published on the topic of upper urinary tract urothelial carcinoma (UTUC). This is a recent review of the available literature of the last 3 years. A systematic Medline/PubMed search on UTUC including limits for clinical trials and randomized, controlled trials was performed for English-language articles using the keywords ‘upper urinary tract carcinoma’, ‘nephroureterectomy’, ‘laparoscopic’, ‘ureteroscopy’, ‘percutaneous’, ‘renal pelvis’, ‘ureter’ and their combinations from January 2008 to December 2010. Additional selected reports from 2007 were included. Case reports and non-English literature were excluded. Publications were mostly retrospective, including some large, multicentre studies from the Upper Tract Urothelial Carcinoma Collaboration (UTUCC). The authors of this article are members of the UTUCC. Altogether, 92 original articles dealing with UTUC were identified and summarized. The vast majority of the available literature has a low level of evidence (level IV), although many multicentre studies tried to overcome the problem of low numbers by pooling data. It was concluded that in the last 3 years our knowledge regarding UTUC has increased dramatically, although new study concepts allowing us to increase the level of evidence are needed.