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NMR-spectroscopic, structural and theoretical data of cyclic alkyl(amino)iminate (CAAI)-stabilised boranes synthesised by halosilane elimination from CAAI–SiMe3 and haloborane precursors highlight the excellent σ- and π-electron donor ability of CAAIs.

Purpose Resection is guideline recommended in stage I small-cell lung cancer (SCLC) but not in stage II. In this stage, patients are treated with a non-surgical approach. The aim of this meta-analysis was to assess the role of surgery in both SCLC stages. Surgically treated patients were compared to non-surgical controls. Five-year survival rates were analysed. Methods A systematic literature search was performed on December 01, 2021 in Medline, Embase and Cochrane Library. Studies published since 2004 on the effect of surgery in SCLC were considered and assessed using ROBINS-I. We preformed I2-tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. Results Out of 6826 records, we identified seven original studies with a total of 15,170 patients that met our inclusion criteria. We found heterogeneity between these studies and ruled out any publication bias. Patient characteristics did not significantly differ between the two groups (p-value > 0.05). The 5-year survival rates in stage I were 47.4 ± 11.6% for the ‘surgery group’ and 21.7 ± 11.3% for the ‘non-surgery group’ (p-value = 0.0006). Our analysis of stage II SCLC revealed a significant survival benefit after surgery (40.2 ± 21.6% versus 21.2 ± 17.3%; p-value = 0.0474). Conclusion Based on our data, the role of surgery in stage I and II SCLC is robust, since it improves the long-term survival in both stages significantly. Hence, feasibility of surgery as a priority treatment should always be evaluated not only in stage I SCLC but also in stage II, for which guideline recommendations might have to be reassessed.

Loss of LEPR function (LOF) in mammals leads to diverse phenotypes including morbid obesity and infertility while zebrafish show relatively minor phenotypes. This however allows the study of LEPR LOF in the absence of the detrimental effects of hyperglycemia or obesity. Here, we show evidence that leptin plays a role in the central as well as peripheral regulation of the hypothalamic–pituitary–gonadal (HPG) axis in zebrafish. Animals with a Lepr LOF show dysregulated pituitary HPG genes as well as evidence that oocytes mature slower and/or exhibit an increased rate of atresia. In culture, Lepr LOF attenuates the effect of 17α-20β-dihydroxy-4 pregnen-3-one in promoting germinal vesicle breakdown (GVBD) and increases the rate of GVBD as well as attenuates the rate of oocyte atresia.

Purpose The recommended treatment for small-cell lung cancer (SCLC) currently is surgery in stage I disease. We wondered about stage II SCLC and present a meta-analysis on mean-survival of patients that underwent surgery for stage I and II compared to controls. Methods A systematic literature search was performed on December 01st 2021 in Medline, Embase and Cochrane Library. We considered studies published on the effect of surgery in SCLC since 2004 and assessed them using ROBINS-I. We preformed I2-tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. Results Out of 6826 records, seven studies with a total of 11,241 patients (‘surgery group’: 3911 patients; ‘non-surgery group’: 7330; treatment period: 1984–2015) were included. Heterogeneity between the studies was revealed in absence of any publication bias. Patient characteristics did not differ between the groups (p-value > 0.05). The mean-survival in an analysis of patients in stage I was 36.7 ± 10.8 months for the ‘surgery group’ and 20.3 ± 5.7 months for the ‘non-surgery group’ (p-value = 0.0084). A combined analysis of patients in stage I and II revealed a mean-survival of 32.0 ± 16.7 months for the ‘surgery group’ and 19.1 ± 6.1 months for the ‘non-surgery group’ (p-value = 0.0391). In a separate analysis of stage II, we were able to demonstrate a significant survival benefit after surgery (21.4 ± 3.6 versus 16.2 ± 3.9 months; p-value = 0.0493). Conclusion Our meta-analysis shows a significant survival benefit after surgery not only in the recommended stage I but also in stage II SCLC. Our data suggests that both stages should be considered for surgery of early SCLC.

Purpose Preoperative pulmonary function testing is mandatory for non-small cell lung cancer (NSCLC) surgery. The predicted postoperative FEV1 (ppoFEV1) is used for further risk stratification. We compared the ppoFEV1 with the postoperative FEV1 (postFEV1) in order to improve the calculation of the ppoFEV1. Methods 87 patients voluntarily received an FEV1 assessment 1 year after surgery. ppoFEV1 was calculated according to the Brunelli calculation. Baseline characteristics and surgical procedure were compared in a uni- and multivariate analysis between different accuracy levels of the ppoFEV1. Parameters which remained significant in the multinominal regression analysis were evaluated for a modification of the ppoFEV1 calculation. Results Independent factors for a more inaccurate ppoFEV1 were preoperative active smoking (odds ratio (OR) 4.1, confidence interval (CI) 3.6–6.41; p = 0.01), packyears (OR 4.1, CI 3.6–6.41; p = 0.008), younger age (OR 1.1, CI 1.01–1.12; p = 0.03), and patients undergoing pneumectomy (OR 5.55, CI 1.35–23.6; p = 0.01). For the customized ppoFEV1 we excluded pneumonectomies. For patients $$1-\left(\frac{\text{Lung segments resected} + 1}{\text{Total number of segments}}\right)$$ 1 - Lung segments resected + 1 Total number of segments . For actively smoking patients with more than 30 packyears we subtracted one lung segment from the calculation ppoFEV1 = PreFEV1 × $$1-\left(\frac{\text{Lung segments resected} - 1}{\text{Total number of segments}}\right)$$ 1 - Lung segments resected - 1 Total number of segments . Conclusion We were able to enhance the predictability of the ppoFEV1 with modifications. The modified ppoFEV1 (1.828 l ± 0.479 l) closely approximates the postFEV1 of 1.823 l ± 0.476 l, (0.27%) while the original ppoFEV1 calculation is at 1.78 l ± 0.53 (2.19%). However, if patients require pneumectomy, more complex techniques to determine the ppoFEV1 should be included to stratify risk.

In rare diseases such as adrenocortical carcinoma (ACC), in silico analysis can help select promising therapy options. We screened all drugs approved by the FDA and those in current clinical studies to identify drugs that target genomic alterations, also known to be present in patients with ACC. We identified FDA-approved drugs in the My Cancer Genome and National Cancer Institute databases and identified genetic alterations that could predict drug response. In total, 155 FDA-approved drugs and 905 drugs in clinical trials were identified and linked to 375 genes of 89 TCGA patients. The most frequent potentially targetable genetic alterations included TP53 (20%), BRD9 (13%), TERT (13%), CTNNB1 (13%), CDK4 (7%), FLT4 (7%), and MDM2 (7%). We identified TP53-modulating drugs to be possibly effective in 20–26% of patients, followed by the Wnt signaling pathway inhibitors (15%), Telomelysin and INO5401 (13%), FHD-609 (13%), etc. According to our data, 67% of ACC patients exhibited genomic alterations that might be targeted by FDA-approved drugs or drugs being tested in current clinical trials. Although there are not many current therapy options directly targeting reported ACC alterations, this study identifies emerging options that could be tested in clinical trials.

Herein we describe the first examples of isolable electron‐precise diboranes(4) that bear azide moieties: the acyclic 1,2‐diazido‐1,2‐bis(dimethylamino)diborane(4) and the cyclic 1,4‐diaryl‐2,3‐diazido‐1,4‐diaza‐2,3‐diborinines (aryl=mesityl, 2,6‐xylyl, 4‐tolyl). The reported examples are not only stable enough to be observed and isolated (putative transient diborane(4) azides previously reported by our group spontaneously decompose even below room temperature), but some of them are even robust enough to undergo controlled pyrolysis without explosive decomposition at temperatures well above 100 °C. In two cases, the controlled pyrolysis allows the isolation of complex diazaboretidines, which are the apparent dimerization products of endocyclic boryl‐iminoboranes., Potentially explosive yet mild‐mannered! The synthesis and reactivity of diamino‐substituted diborane(4) diazides, the first diborane(4) azides, is reported. Despite the presence of energetic and oxidizing azide groups and of reactive B−B bonds, they are astonishingly robust. The species do not decompose below 100 °C. Two diazides could be pyrolyzed in a controlled manner to diazadiboretidines, the dimerization product of transient iminoboranes.

BackgroundSo far only trastuzumab, pembrolizumab and ramucirumab have been approved by the FDA for targeted therapy in gastric cancer (GC). Here we report on potential targeted therapy options for gastric adenocarcinoma based on a novel analysis of “The Cancer Genome Atlas (TCGA)” database.MethodsOne hundred two FDA-approved targeted cancer drugs were compiled and molecular targets defined. Drugs were considered as potentially effective if targeted genes showed (1) an increase in copy number, (2) gain of function with oncogene activation, (3) specific alterations responsive to approved drugs. Additionally, genetic changes that confer drug resistance and/or sensitivity were evaluated.ResultsFifty percentage of patients with GC may be treatable with non-GC but FDA-approved targeted cancer therapies. The major drug identified in our in silico study for GC is copanlisib, a PI3K inhibitor. In the TCGA patient database, our genetically based drug response prediction identified more patients with alterations sensitive to copanlisib compared to the already-GC-approved drug trastuzumab (20%, 78 out of 393 patients, vs. trastuzumab: 13%, 52 of 393 patients), which is mainly due to the high incidence of PIK3CA gain of function mutations within mutation hot spots.ConclusionOur results demonstrate that various currently FDA-approved drugs might be candidates for targeted therapy of GC. For clinical trials, cancer patients should be selected based on the genomic profile of their tumor.

Obesity and metabolic syndrome are of increasing global concern. In order to understand the basic biology and etiology of obesity, research has turned to animals across the vertebrate spectrum including zebrafish. Here, we carefully characterize zebrafish in a long-term obesogenic environment as well as zebrafish that went through early lifetime caloric restriction. We found that long-term obesity in zebrafish leads to metabolic endpoints comparable to mammals including increased adiposity, weight, hepatic steatosis and hepatic lesions but not signs of glucose dysregulation or differences in metabolic rate or mitochondrial function. Malnutrition in early life has been linked to an increased likelihood to develop and an exacerbation of metabolic syndrome, however fish that were calorically restricted from five days after fertilization until three to nine months of age did not show signs of an exacerbated phenotype. In contrast, the groups that were shifted later in life from caloric restriction to the obesogenic environment did not completely catch up to the long-term obesity group by the end of our experiment. This dataset provides insight into a slowly exacerbating time-course of obesity phenotypes.

The leptin system plays a crucial role in the regulation of appetite and energy homeostasis in vertebrates. While the phenotype of morbid obesity due to leptin (Lep) or leptin receptor (LEPR) loss of function is well established in mammals, evidence in fish is controversial, questioning the role of leptin as the vertebrate adipostat. Here we report on three (Lepr) loss of function (LOF) and one leptin loss of function alleles in zebrafish. In order to demonstrate that the Lepr LOF alleles cannot transduce a leptin signal, we measured socs3a transcription after i.p. leptin which is abolished by Lepr LOF. None of the Lepr/Lepa LOF alleles leads to obesity/a body growth phenotype. We explore possible reasons leading to the difference in published results and find that even slight changes in background genetics such as inbreeding siblings and cousins can lead to significant variance in growth.

The growing interest in non-alcoholic and low alcohol beers (NABLAB) has fuelled research into innovative production methods. One means to produce NABLAB is through limited fermentation by non-Saccharomyces yeasts which have a naturally low fermentative capacity in cereal-based wort substrates. At the same time, adjunct brewing, the partial replacement of barley malt on the grain bill, enjoys growing popularity. In this study, 13 cereals, pseudocereals, and pulses were investigated for their suitability to produce a wort with limited amounts of fermentable sugars. Subsequently, the fermentation performance of two non-Saccharomyces yeast strains, namely Cyberlindnera subsufficiens C6.1 and Lachancea fermentati KBI 12.1, in the produced worts was investigated and compared to that of a brewers’ yeast strain. The worts were produced by harnessing endogenous amylolytic enzyme activity or the addition of an external amylase and analysed for their sugar composition and free amino acids (FAA) profile. All alternative substrates without endogenous β-amylase activity were found to be suitable for producing worts with a high proportion of unfermentable sugars. However, the extract yield was low for the pulses and most worts exhibited a low and/or unbalanced FAA profile. The ethanol production was limited and mostly dependent on the sugar spectrum of the worts and the sugar utilization characteristics of the applied yeast strains. The (partial) substitution of barley with alternative substrates when producing NABLAB by non-Saccharomyces yeast can be a means to alter the sugar and FAA profile of the wort, but must be considered in concert with the yeast strains’ characteristics.

In brewing research, non-Saccharomyces yeasts have gained attention in recent years, owing to their potential to influence the characteristics and flavor of beer. The Lachancea genus possesses an u...

Microbial spoilage of alcohol-free and low-alcohol beers, beer-mixed beverages, and soft drinks is most commonly caused by yeast. Yeast-related biofilms are therefore a serious problem in t...

The aim of this study was to identify yeast strains and hop-tolerant lactic acid bacteria from Bozo, a traditional Kyrgyz-fermented beverage that has been described as a predecessor of today’s beer. The isolated cultures were screened for their potential use in beer fermentation. A functional beer beverage made from an ancestor of beer could prove innovative for craft brewing. The cultures were isolated using a selective medium (VLB-S7S-Agar, 10 International Bittering Units), as beer includes hop acids that are lethal to many lactic acid bacteria. The application of polymerase chain reaction (PCR) techniques (real-time PCR, PCR sequencing of a partial fragment of the 16S rDNA) revealed the lactic acid bacteria Lactobacillus plantarum, Lactobacillus casei, and Pediococcus parvulus as well as three different strains of the yeast species S. To produce a beer similar to the traditional Kyrgyz beverage Bozo, all-malt wort was fermented using pure cultures of the isolated microorganisms. One strain of ...

Background: Patients undergoing transcatheter aortic valve replacement (TAVR) are mostly elderly patients with substantial comorbidities. Established risk scores are not validated for TAVR and collectives with elderly patients making periprocedural risk stratification difficult. Serum albumin is known to be an indicator for malnutrition and frailty and is simple to measure, independent of physician’s bias. Using serum albumin as a preoperative marker for postoperative complications might help estimating morbidity and mortality of these patients. Methods: A total of 457 patients with severe symptomatic aortic stenosis undergoing TAVR at our institution in a period from January 2014 to December 2015 were included in this retrospective study. Baseline characteristics as well as preoperative laboratory parameters were registered. Postoperative morbidity and 30-day mortality were analyzed as primary end points. Enrolled patients with preoperative low serum albumin ( Results: Among 457 patients, 51 (11%) presented pre-procedural low serum albumin and 406 (89%) had normal serum albumin. Patients’ mean age was 81±6 years and 50% of them were male. Postoperative complications such as requirement of blood transfusions (63% versus 33%, P Conclusions: Preoperative low serum albumin might be an indicator for higher morbidity and mortality in patients undergoing TAVR.

Radical lymphadenectomy is crucial in operations for non-small cell lung cancer (NSCLC). Usually pN1 and pN2 lymph nodes are affected consecutively (N1N2). Nevertheless, pN2 metastases may also occur in the absence of pN1 as skip-N2 metastases (N0N2). Here we compare the long-term survival of N1N2- and N0N2 patients.464 patients underwent surgery for NSCLC at our institution between 2012 and 2017. We retrospectively reviewed data of pN2 stage patients (n = 68). Patients with N1N2 (n = 39) were compared to N0N2 (n = 29) patients. 1-, 3-and 5-year survival rates were measured. Survival was assessed by Kaplan-Meier curves and the cox proportional hazards model was used to identify prognostic factors for overall survival. All patients received adjuvant chemoradiation therapy according to European guidelines.The baseline characteristics did not differ between groups. We observed no differences in the histology, localization, or gender in our cohort. N0N2 patients showed significantly better 1- (N1N2: 82.4% vs. N0N2 100%; p = 0.001), 3- (14.7% vs. 63.6%; p=0.001) and 5-year (9.4% vs. 43.8%; p = 0.001) survival rates. Tumor size (Hazard ratio (HR) 1.46, Confidence interval (CI 95%) 1.03-2.04; p = 0.03) and the occurrence of N1N2 (HR 4.26, CI 2.04-8.91; p 0.0001) were independent prognostic factors for worse long-term survival. The Kaplan-Meier curves showed a reduced overall survival for N1N2 patients (log-rank N1N2, N0N2 p 0.0001).N1N2 patients have a significantly worse prognosis compared to N0N2 patients. This will aid to classify the heterogeneous pN2-NSCLC patient population more precisely. Further, multimodal therapy should be considered for N1N2 patients.

Non-alcoholic beer (NAB) is enjoying growing demand and popularity due to consumer lifestyle trends and improved production methods. In recent years in particular, research into the application of non-Saccharomyces yeasts to produce NAB via limited fermentation has gained momentum. Non-Saccharomyces yeasts are known to produce fruity aromas, owing to a high ester production. This trait could be harnessed to mask the often-criticized wort-like off-flavor of NAB produced via limited fermentation. Six Cyberlindnera strains were characterized and screened in wort extract. Four of the six strains produced a pleasant, fruity aroma while exhibiting low ethanol production. The strain Cyberlindnera subsufficiens C6.1 was chosen for fermentation optimization via response surface methodology (RSM) and a pilot-scale (60 L) brewing trial with subsequent sensory evaluation. A low fermentation temperature and low pitching rate enhanced the fruitiness and overall acceptance of the NAB. The NAB (0.36% ABV) produced on pilot-scale was significantly more fruity and exhibited a significantly reduced wort-like off-flavor compared to two commercial NABs. This study demonstrated the suitability of Cyberlindnera subsufficiens to produce a fruity NAB, which can compete with commercial NABs. The outcome strengthens the position of non-Saccharomyces yeasts as a serious and applicable alternative to established methods in NAB brewing.

The significance of postoperatively diagnosed Lymphangiosis Carcinomatosa (L1) as an independent risk factor for long-term survival in Non-Small Cell Lung Cancer (NSCLC) remains controversial. We analyzed the effect of L1 on postoperative survival in stage I, II and III NSCLC-patients.We investigated all consecutive patients with NSCLC between January 2012 and December 2019 who underwent an anatomical resection and radical lymphadenectomy at our institute. L1-were compared to L0-patients. All patients received adjuvant chemotherapy in accordance with European guidelines. 3- and 5- year survival rates and median-survival were assessed. To investigate whether L1 is an independent risk factor, we carried out a multivariate cox regression and a pair-match analysis looking at different properties such as TNM.A total of 641 patients (L0: 74%; L1: 26%) were analyzed. Baseline characteristics were comparable between groups. The mean age was 65.3 ± 10.2 years and 64.9 ± 9.4 years in the L0 and L1-groups respectively (p-value = 0.703). 58.5% of L0-patients were male (L1: 62.7%; p-value = 0.351). Overall survival in the L1-group was significantly shorter compared to the L0-group (L1: 42.3 ± 2.8; L0: 67.6 ± 2.1 months; p-value0.0001). We confirmed this finding in a pair-matched analysis (L0: 73.9 ± 4.7 months; L1: 42.2 ± 4.2; p-value = 0.009). 3- and 5-year survival were significantly shorter for L1-patients (3-year: L0: 65.9%; L1: 35.9%; p-value0.0001) (5-year: L0: 34.9%; L1: 7.5%; p-value0.0001).L1 is an independent risk factor for long-term survival of patients with NSCLC. This cohort supports that the L0/L1 status should be included in pathological reports. We suggest to further include L0/L1-status in guideline recommendations for NSCLC patients.

Agouti related protein (AgRP) is a hypothalamic regulator of food consumption in mammals. However, AgRP has also been detected in circulation, but a possible endocrine role has not been examined. Zebrafish possess two agrp genes; hypothalamically expressed agrp1, considered functionally equivalent to the single mammalian agrp, and agrp2, which is expressed in pre-optic neurons and uncharacterized pineal gland cells, and whose function is not well understood. By ablation of AgRP1-expressing neurons and knockout of the agrp1 gene, we show that AgRP1 stimulates food consumption in the zebrafish larvae. Single-cell sequencing of pineal agrp2-expressing cells revealed molecular resemblance to retinal-pigmented epithelium cells and anatomic analysis shows that these cells secrete peptides, possibly into the cerebrospinal fluid. Additionally, based on AgRP2 peptide localization and gene knockout analysis, we demonstrate that pre-optic AgRP2 is a neuroendocrine regulator of the stress axis that reduces cortisol secretion. We therefore suggest that the ancestral role of AgRP was functionally partitioned in zebrafish by the two AgRPs; with AgRP1 centrally regulating food consumption, while AgRP2 acts as a neuroendocrine factor regulating the stress axis.

Recently there has been increased interest in using non-Saccharomyces yeasts to ferment beer. The worldwide growth of craft beer and microbreweries has revitalised the use of different yeast strains with a pronounced impact on aroma and flavour. Using non-conventional yeast gives brewers a unique selling point to differentiate themselves. Belgian brewers have been very successful in using wild yeasts and mixed fermentations that often contain non-Saccharomyces yeasts. Historically, ancient beers and beers produced before the domestication of commonly used Saccharomyces strains most likely included non-Saccharomyces species. Given the renewed interest in using non-Saccharomyces yeasts to brew traditional beers and their potential application to produce low-alcohol or alcohol-free beer, the fermentation and flavour characteristics of different species of non-Saccharomyces pure culture yeast were screened for brewing potential (Brettanomyces anomalus and bruxellensis, Candida tropicalis and shehatae, Saccharomycodes ludwigii, Torulaspora delbrueckii, Pichia kluyveri, Zygosaccharomyces rouxii). Alcohol-free beer is already industrially produced using S. ludwigii, a maltose-negative species, which is a good example of the introduction of non-Saccharomyces yeast to breweries. Overall, non-Saccharomyces yeasts represent a large resource of biodiversity for the production of new beers and have the potential for wider application to other beverage and industrial applications. Almost all of the trials reviewed were conducted with varying fermentation parameters, which plays an important role in the outcome of the studies. To understand these impacts all trials were described with their major fermentation parameters. Copyright © 2016 The Institute of Brewing & Distilling

Beer quality is highly dependent upon yeast condition. Consequently, breweries should consider the quality of the pitching yeast. Spoilage yeasts such as wild types of Saccharomyces cerevisiae, S. ...

Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.