Carbon–carbon bond formation is the key reaction for organic synthesis to construct the carbon framework of organic molecules. The review gives a selection of biocatalytic C–C-bond-forming reactions ...which have been investigated during the last 5 years and which have already been proven to be applicable for organic synthesis. In most cases, the reactions lead to products functionalized at the site of C–C-bond formation (e.g., α-hydroxy ketones, aminoalcohols, diols, 1,4-diketones, etc.) or allow to decorate aromatic and heteroaromatic molecules. Furthermore, examples for cyclization of (non)natural precursors leading to saturated carbocycles are given as well as the stereoselective cyclopropanation of olefins affording cyclopropanes. Although many tools are already available, recent research also makes it clear that nature provides an even broader set of enzymes to perform specific C–C coupling reactions. The possibilities are without limit; however, a big library of variants for different types of reactions is required to have the specific enzyme for a desired specific (stereoselective) reaction at hand.
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IJS, KILJ, NUK, PNG, UL, UM
The health benefits of carefully restricting the energy intake in a strategic manner whilst avoiding malnutrition are widely discussed. In the recent years, the great impact of the gut microbiota on ...its host has been clarified more and more. Since the gut microbiota produces a number of metabolites and molecules that can affect host metabolism, modulating it with dietary restriction can influence the health and the progression of disease of its host on various levels. This review comprises 15 studies investigating the effect of different variants of fasting and caloric restriction on the gastrointestinal microbiome and its metabolites. The data suggest that changing the gut microbiota composition by dietary restriction has the potential to positively influence the progression of several diseases such as obesity, diabetes, neurological diseases or inflammatory bowel disease. Finally, the relevance of the findings for clinical practice is evaluated and approaches for future research are proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Friedel–Crafts acylation is a broadly applied reaction that can be conducted using various types of catalyst. However, a biocatalytic alternative has only been reported recently. In this study, ...the scope of acetyl donors is described, showing that, in addition to vinyl acetate derivatives, phenyl esters are also suitable donors. Furthermore, it was found that various amines enhance the reaction, whereby the effect do not seem to be correlated to the pH but to the structure of the donor. For instance, 1,4‐diazabicyclo2.2.2octane (DABCO) turned out to be a viable alternative to imidazole; however the former performed best at pH 9.85, whereas the latter performed best at pH 8.3.
A biocatalytic Friedel–Crafts‐like acylation is described. The scope of the activating groups of the acetyl donors as well as the influence and effect of amines as additive on the reaction are studied.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Friedel–Crafts acylation is commonly used for the synthesis of aryl ketones, and a biocatalytic version, which may benefit from the chemo‐ and regioselectivity of enzymes, has not yet been ...introduced. Described here is a bacterial acyltransferase which can catalyze Friedel–Crafts C‐acylation of phenolic substrates in buffer without the need of CoA‐activated reagents. Conversions reach up to >99 %, and various C‐ or O‐acyl donors, such as DAPG or isopropenyl acetate, are accepted by this enzyme. Furthermore the enzyme enables a Fries rearrangement‐like reaction of resorcinol derivatives. These findings open an avenue for the development of alternative and selective C−C bond formation methods.
Order up on Fries: The biocatalytic acylation of resorcinol substrates, catalyzed by an acyltransferase, leads to C‐acylated products. The Friedel–Crafts bio‐C‐acylation allows use of simple activated esters, such as isopropenyl acetate, as an acyl source. Additionally the enzyme enables a Fries rearrangement‐like reaction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Im Kontext der kulturwissenschaftlichen Gedächtnisforschung widmet sich diese interdisziplinär ausgerichtete Reihe dem Verhältnis von Medien und kultureller Erinnerung. Die hier vorgestellten Studien ...behandeln die ganze Bandbreite der durch Medien konstruierten, tradierten und verbreiteten Erinnerung. Schrift und Bild, das Kino und die 'neuen' digitalen Medien, Intermedialität, Transmedialität und Remediation sowie die sozialen, zunehmend transnationalen und transkulturellen, Kontexte der mediatisierten Erinnerung gehören zu den Forschungsinteressen der Reihe. Ziel ist es, eine internationale Plattform für die interdisziplinäre Medien- und Gedächtnisforschung zu schaffen. Eingereichte Manuskripte werden im peer review Verfahren durch externe Experten begutachtet. Den Herausgebern, Astrid Erll (Goethe-Universität Frankfurt am Main) und Ansgar Nünning (Justus-Liebig-Universität Gießen) ist ein internationaler Beirat aus renommierten Wissenschaftlern assoziiert: * Aleida Assmann (Universität Konstanz) * Mieke Bal (University of Amsterdam) * Vita Fortunati (University of Bologna) * Richard Grusin (University of Wisconsin-Milwaukee) * Udo Hebel (Universität Regensburg) * Andrew Hoskins (University of Glasgow) * Wulf Kansteiner (Binghamton University) * Alison Landsberg (George Mason University) * Claus Leggewie (Kulturwissenschaftliches Institut Essen) * Jeffrey Olick (University of Virginia) * Susannah Radstone (University of South Australia) * Ann Rigney (Utrecht University) * Michael Rothberg (University of Illinois) * Werner Sollors (Harvard University) * Frederic Tygstrup (University of Copenhagen) * Harald Welzer (Kulturwissenschaftliches Institut Essen)
Background
The objective of this study was to investigate the feasibility and efficacy of image‐guided moderately hypofractionated thoracic radiotherapy (hypo‐IGRT) in patients with non–small cell ...lung cancer (NSCLC) with poor performance status and severely limited pulmonary function and reserve.
Methods
Consecutive inoperable patients who had node‐positive, stage IIB‐IIIC (TNM, 8th edition) or recurrent NSCLC, had an Eastern Cooperative Oncology Group performance status ≥1, and had a forced expiratory volume in 1 second (FEV1) ≤1.0 L, had a single‐breath diffusing capacity of the lung for carbon monoxide (DLCO‐SB) ≤40% and/or on long‐term oxygen therapy were analyzed. All patients received hypofractionated IGRT to a total dose of 42.0 to 49.0 Gy/13 to 16 fractions (2.8‐3.5 Gy/fraction) (equivalent dose in 2‐Gy fractions/biologically effective dose α/β = 10 = 45.5‐55.1 Gy/54.6‐66.2 Gy) alone. Patients were monitored closely for nonhematological toxicity, which was classified per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Results
Between 2014 and 2021, 47 consecutive patients with a median age of 72 years (range, 52.2‐88 years) were treated. At baseline, the median FEV1, vital capacity, and DLCO‐SB were 1.17 L (range, 0.69‐2.84 L), 2.34 L (range, 1.23‐3.74 L), and 35% predicted (range, 13.3%‐69.0%), respectively. The mean and median planning target volumes were 410.8 cc (SD, 267.1 cc) and 315.4 cc (range, 83.4‐1174.1 cc). With a median follow‐up of 28.9 months (range, 0.5‐90.6 months) after RT, the median progression‐free survival (PFS)/overall survival (OS) and 6‐ and 12‐month PFS/OS rates were 10.4 months (95% CI, 7‐13.8 months)/18.3 months (95% CI, 9.2‐27.4 months), 70%/89.4%, and 38.8%/66%, respectively. Treatment was well tolerated with only 1 case each of grade 3 pneumonitis and esophagitis. No toxicity greater than grade 3 was observed.
Conclusions
Patients with inoperable node‐positive NSCLC, a poor performance status, and severely limited lung function can be safely and effectively treated with individualized moderately hypofractionated IGRT. The achieved survival rates for this highly multimorbid group of patients were encouraging.
In this article, the knowledge gap between the management of patients with unfavorable risk factors and severely limited pulmonary function and reserve (forced expiratory volume in 1 second ≤1 L and/or single‐breath diffusing capacity of the lung for carbon monoxide ≤40% predicted and/or on long‐term oxygen therapy) is addressed. In light of encouraging results, a clinical pathway is proposed for the management of these high‐risk patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose or Objective
To provide a comprehensive recurrence and toxicity analysis of patients treated with radiotherapy alone for stage I/II (Ann‐Arbor classification) indolent orbital lymphoma.
...Material and Methods
We retrospectively reviewed the medical charts of 46 patients (and 51 orbits) treated at our centre with radiotherapy between 1995 and 2012 for biopsy‐proven stage I/IIE primary orbital lymphomas. We evaluated treatment response and performed a comprehensive toxicity analysis with correlation to delivered radiation dose.
Results
At diagnosis, the median age was 63.5 years (range: 20–92). At initial diagnosis 43 and 3 patients had unilateral, synchronous bilateral involvement while there were 2 cases of contralateral metachronous failure. The predominant histological subtype was extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue in 42 (91.3%), follicular in 1 (2.2%), lymphoplasmacytic lymphoma in 1 (2.2%) and other indolent histology in 2 (4.3%) patients. Most lymphomas were located in the conjunctiva (18/35.3%) or eyelids (18/35.3%). Thirty‐eight (82.6%) patients presented with stage I while 8/46 (17.4%) with stage II disease. The median radiation dose was 39.6 Gy (range: 21.6–48.6 Gy) delivered in 1.8–2 Gy single fractions.
At a median follow‐up of 83 months (range: 7–258 months), the complete remission rate was 98%. A local relapse was observed in 2/51 (3.9%) orbits and 4/46 (8.7%) patients had systemic relapse. The 5‐ and 10‐year PFS rates were 79.2% (95% CI: 73.0%–85.4%) and 67.6% (95% CI: 59.4%–75.8%); 5‐ and 10‐year OS was 83.6% (95% CI: 77.9%–89.3%) and 76.5% (95% CI: 69.4%–83.6%), respectively. In total, 66 acute toxicity events (all‐grade) were observed: 5/51 (9.8%) ≥G2 acute conjunctivitis, 2/51 (3.9%) cases of G2 acute keratitis, 1/51 (2%) cases of ≥G2 ophthalmagia and 12/51 (23.5%) cases of ≥G2 xerophthalmia. Furthermore, 45 chronic adverse events were observed in 34/51 (66.7%) irradiated orbits with 30 late adverse events attributed to cataract.
Conclusion
Our analysis confirms the role of radiotherapy alone at lower doses in the treatment of indolent orbital lymphomas. Further research is required to assess the efficacy of ultra‐low‐dose radiotherapy and anti‐CD20 monoclonal antibodies to further mitigate long‐term sequelae.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
C−C bond‐forming reactions are key transformations for setting up the carbon frameworks of organic compounds. In this context, Friedel–Crafts acylation is commonly used for the synthesis of aryl ...ketones, which are common motifs in many fine chemicals and natural products. A bacterial multicomponent acyltransferase from Pseudomonas protegens (PpATase) catalyzes such Friedel–Crafts C‐acylation of phenolic substrates in aqueous solution, reaching up to >99 % conversion without the need for CoA‐activated reagents. We determined X‐ray crystal structures of the native and ligand‐bound complexes. This multimeric enzyme consists of three subunits: PhlA, PhlB, and PhlC, arranged in a Phl(A2C2)2B4 composition. The structure of a reaction intermediate obtained from crystals soaked with the natural substrate 1‐(2,4,6‐trihydroxyphenyl)ethanone together with site‐directed mutagenesis studies revealed that only residues from the PhlC subunits are involved in the acyl transfer reaction, with Cys88 very likely playing a significant role during catalysis. These structural and mechanistic insights form the basis of further enzyme engineering efforts directed towards enhancing the substrate scope of this enzyme.
Crystal structures of a dodecameric enzyme: This multimeric enzyme consists of three subunits: PhlA, PhlB, and PhlC, arranged in a Phl(A2C2)2B4 composition. The PhlC subunit catalyzes the Friedel–Crafts C‐acylation of phenolic substrates in aqueous solution without the need for CoA‐activated reagents.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, leading to a string of approvals in recent years. Herein, a narrative review on the role ...of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in the ever-evolving treatment landscape of advanced NSCLC is presented.
Methods
This comprehensive review will begin with an introduction into current treatment paradigms incorporating ICIs; the evolution of CT-based criteria; moving onto novel phenomena observed with ICIs and the current state of hybrid imaging for diagnosis, treatment planning, evaluation of treatment efficacy and toxicity in advanced NSCLC, also taking into consideration its limitations and future directions.
Conclusions
The advent of ICIs marks the dawn of a new era bringing forth new challenges particularly vis-à-vis treatment response assessment and observation of novel phenomena accompanied by novel systemic side effects. While FDG PET/CT is widely adopted for tumor volume delineation in locally advanced disease, response assessment to immunotherapy based on current criteria is of high clinical value but has its inherent limitations. In recent years, modifications of established (PET)/CT criteria have been proposed to provide more refined approaches towards response evaluation. Not only a comprehensive inclusion of PET-based response criteria in prospective randomized controlled trials, but also a general harmonization within the variety of PET-based response criteria is pertinent to strengthen clinical implementation and widespread use of hybrid imaging for response assessment in NSCLC.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Purpose
Nodal recurrent prostate cancer (PCa) represents a common state of disease, amenable to local therapy. PSMA-PET/CT detects PCa recurrence at low PSA levels. The aim of this study was to ...evaluate the outcome of PSMA-PET/CT-based salvage radiotherapy (sRT) for lymph node (LN) recurrence.
Methods
A total of 100 consecutive patients treated with PSMA-PET/CT-based salvage elective nodal radiotherapy (sENRT) for LN recurrence were retrospectively examined. Patients underwent PSMA-PET/CT scan due to biochemical persistence (bcP, 76%) or biochemical recurrence (bcR, 24%) after radical prostatectomy (RP). Biochemical recurrence-free survival (BRFS) defined as PSA < post-RT nadir + 0.2 ng/ml and distant metastasis-free survival (DMFS) were calculated using the Kaplan–Meier method and uni- and multivariate analysis was performed.
Results
Median follow-up was 37 months. Median PSA at PSMA-PET/CT was 1.7 ng/ml (range 0.1–40.1) in patients with bcP and 1.4 ng/ml (range 0.3–5.1) in patients with bcR. PSMA-PET/CT detected 1, 2, and 3 or more LN metastases in 35%, 23%, and 42%, respectively. Eighty-three percent had only pelvic, 2% had only paraaortic, and 15% had pelvic and paraaortic LN metastases. Cumulatively, a total dose converted to EQD2
1.5 Gy
of 66 Gy (60–70 Gy) was delivered to the prostatic fossa, 70 Gy (66–72 Gy) to the local recurrence, if present, 65.1 Gy (56–66 Gy) to PET-positive lymph nodes, and 47.5 Gy (42.4–50.9 Gy) to the lymphatic pathways. Concomitant androgen deprivation therapy (ADT) was administered in 83% of patients. One-, 2-, and 3-year BRFS was 80.7%, 71.6%, and 65.8%, respectively. One-, 2-, and 3-year DMFS was 91.6%, 79.1%, and 66.4%, respectively. In multivariate analysis, concomitant ADT, longer ADT duration (≥ 12 vs. < 12 months) and LN localization (pelvic vs. paraaortic) were associated with improved BRFS and concomitant ADT and lower PSA value before sRT (< 1 vs. > 1 ng/ml) with improved DMFS, respectively. No such association was seen for the number of affected lymph nodes.
Conclusions
Overall, the present analysis shows that the so far, unmatched sensitivity and specificity of PSMA-PET/CT translates in comparably high BRFS and DMFS after PSMA-PET/CT-based sENRT for patients with PCa LN recurrence. Concomitant ADT, duration of ADT, PSA value before sRT, and localization of LN metastases were significant factors for improved outcome.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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