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The SCIP Optimization Suite provides a collection of software packages for mathematical optimization centered around the constraint integer programming framework SCIP . The focus of this paper is on the role of the SCIP Optimization Suite in supporting research. SCIP ’s main design principles are discussed, followed by a presentation of the latest performance improvements and developments in version 8.0, which serve both as examples of SCIP ’s application as a research tool and as a platform for further developments. Further, the paper gives an overview of interfaces to other programming and modeling languages, new features that expand the possibilities for user interaction with the framework, and the latest developments in several extensions built upon SCIP .

Purpose: Surgical workflow and skill analysis are key technologies for the next generation of cognitive surgical assistance systems. These systems could increase the safety of the operation through context-sensitive warnings and semi-autonomous robotic assistance or improve training of surgeons via data-driven feedback. In surgical workflow analysis up to 91% average precision has been reported for phase recognition on an open data single-center video dataset. In this work we investigated the generalizability of phase recognition algorithms in a multicenter setting including more difficult recognition tasks such as surgical action and surgical skill. Methods: To achieve this goal, a dataset with 33 laparoscopic cholecystectomy videos from three surgical centers with a total operation time of 22 h was created. Labels included framewise annotation of seven surgical phases with 250 phase transitions, 5514 occurences of four surgical actions, 6980 occurences of 21 surgical instruments from seven instrument categories and 495 skill classifications in five skill dimensions. The dataset was used in the 2019 international Endoscopic Vision challenge, sub-challenge for surgical workflow and skill analysis. Here, 12 research teams trained and submitted their machine learning algorithms for recognition of phase, action, instrument and/or skill assessment. Results: F1-scores were achieved for phase recognition between 23.9% and 67.7% (n = 9 teams), for instrument presence detection between 38.5% and 63.8% (n = 8 teams), but for action recognition only between 21.8% and 23.3% (n = 5 teams). The average absolute error for skill assessment was 0.78 (n = 1 team). Conclusion: Surgical workflow and skill analysis are promising technologies to support the surgical team, but there is still room for improvement, as shown by our comparison of machine learning algorithms. This novel HeiChole benchmark can be used for comparable evaluation and validation of future work. In future studies, it is of utmost importance to create more open, high-quality datasets in order to allow the development of artificial intelligence and cognitive robotics in surgery.

Aims Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients. Methods and results A total of 50 transplant patients [1–3 years post heart (42), lung (7), or heart–lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness. Conclusions The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients.

Background We report the results of a prospective study on the immunogenicity of a 3rd dose of BNT162b2 in thoracic organ recipients with no or minimal response following a two-dose BNT162b2 vaccination scheme. Methods A total of 243 transplant recipients received a homologue 3rd dose. Anti-SARS-CoV2-immunoglobulins (IgGs) were monitored immediately before (T1), 4 weeks (T2) as well as 2 and 4 months after the 3rd dose. Neutralizing antibody capacity (NAC) was determined at T2. To reveal predictors for detectable humoral response, patients were divided into a positive response group (n = 129) based on the combined criteria of IgGs and NAC above the defined cut-offs at T2—and a group with negative response (n = 114), with both, IgGs and NAC beyond the cut-offs. Results The 3rd dose induced a positive humoral response in 53% of patients at T2, 47% were still non-responsive. Sero-positivity was significantly stronger in patients who presented with weak, but detectable IgGs already prior to the booster (T1), when compared to those with no detectable response at T1. Multivariable analysis identified age > 55 years, a period since transplantation Conclusions Our data indicate that a lack of immunogenicity is linked to the type and extent of maintenance immunosuppression. The necessity of the cumulative immunosuppressive regimen might individually be questioned and possibly be reduced to enhance the chance of an immune response following an additional booster dose.

Despite major progress in breast cancer research, the functional contribution of distinct cancer cell clones to malignant tumor progression and metastasis remains largely elusive. We have assessed clonal heterogeneity within individual primary tumors and metastases and also during the distinct stages of malignant tumor progression using clonal tracking of cancer cells in the MMTV-PyMT mouse model of metastatic breast cancer. Comparative gene expression analysis of clonal subpopulations reveals a substantial level of heterogeneity across and also within the various stages of breast carcinogenesis. The intra-stage heterogeneity is primarily manifested by differences in cell proliferation, also found within invasive carcinomas of luminal A-, luminal B-, and HER2-enriched human breast cancer. Surprisingly, in the mouse model of clonal tracing of cancer cells, chemotherapy mainly targets the slow-proliferative clonal populations and fails to efficiently repress the fast-proliferative populations. These insights may have considerable impact on therapy selection and response in breast cancer patients.

Semantic segmentation of organs and tissue types is an important sub-problem in image based scene understanding for laparoscopic surgery and is a prerequisite for context-aware assistance and cognitive robotics. Deep Learning (DL) approaches are prominently applied to segmentation and tracking of laparoscopic instruments. This work compares different combinations of neural networks, loss functions, and training strategies in their application to semantic segmentation of different organs and tissue types in human laparoscopic images in order to investigate their applicability as components in cognitive systems. TernausNet-11 trained on Soft-Jaccard loss with a pretrained, trainable encoder performs best in regard to segmentation quality (78.31% mean Intersection over Union [IoU]) and inference time (28.07 ms) on a single GTX 1070 GPU.

Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared the bivalent DARPin dimer (DD1) and a DARPin-Fc (DFc) to the monomeric DARPin (DM) and the antibody derived scFv425-Fc (scFvFc) in cell culture and a mouse model. The modular conjugation system, which was successfully applied for the preparation of protein-drug and -dye conjugates, uses bio-orthogonal protein-aldehyde generation by the formylglycine-generating enzyme (FGE). The generated carbonyl moiety is addressed by a bifunctional linker with a pyrazolone for a tandem Knoevenagel reaction and an azide for strain-promoted azide-alkyne cycloaddition (SPAAC). The latter reaction with a PEGylated linker containing a dibenzocyclooctyne (DBCO) for SPAAC and monomethyl auristatin E (MMAE) as the toxin provided the stable conjugates DD1-MMAE (drug-antibody ratio, DAR = 2.0) and DFc-MMAE (DAR = 4.0) with sub-nanomolar cytotoxicity against the human squamous carcinoma derived A431 cells. In vivo imaging of Alexa Fluor 647-dye conjugates in A431-xenografted mice bearing subcutaneous tumors as the SCC model revealed unspecific binding of bivalent DARPins to the ubiquitously expressed EGFR. Tumor-targeting was verified 6 h post-injection solely for DD1 and scFvFc. The total of four administrations of 6.5 mg/kg DD1-MMAE or DFc-MMAE twice weekly did not cause any sequela in mice. MMAE conjugates showed no significant anti-tumor efficacy in vivo, but a trend towards increased necrotic areas (p = 0.2213) was observed for the DD1-MMAE (n = 5).

Multiple, site-specific protein conjugation is increasingly attractive for the generation of antibody-drug conjugates (ADCs). As it is important to control the number and position of cargoes in an ADC, position-selective generation of reactive sites in the protein of interest is required. Formylglycine (FGly) residues are generated by enzymatic conversion of cysteine residues embedded in a certain amino acid sequence motif with a formylglycine-generating enzyme (FGE). The addition of copper ions increases FGE activity leading to the conversion of cysteines within less readily accepted sequences. With this tuned enzyme activity, it is possible to address two different recognition sequences using two aerobic formylglycine-generating enzymes. We demonstrate an improved and facile strategy for the functionalization of a DARPin (designed ankyrin repeat protein) and the single-chain antibody scFv425-Fc, both directed against the epidermal growth factor receptor (EGFR). The single-chain antibody was conjugated with monomethyl auristatin E (MMAE) and carboxyfluorescein (CF) and successfully tested for receptor binding, internalization, and cytotoxicity in cell culture, respectively.

The epidermal growth factor receptor (EGFR) is a transmembrane protein involved in cell signaling processes, and dysregulation of its activity often drives tumor growth. EGFR is a clinically validated tumor marker and target for antibodies and tyrosine kinase inhibitors. We demonstrate that a fusion protein of the natural ligand epidermal growth factor (EGF) with the fluorescent reporter mCherry can be expressed in the cytosol of E. coli in high yields and with a high biological activity. Biophysical characterization by mass spectrometry analysis confirmed three disulfide bonds that are crucial for protein structure. Biolayer interferometry data of the protein-protein interaction of EGF-mCherry with the soluble EGFR are comparable to that of unmodified EGF. Cell culture experiments demonstrated that this fusion replicates all important features of the natural ligand. Finally, fluorescent assays based on EGF-mCherry provided a simple and convenient method to compare EGFR levels on cells and to determine competition of EGFR-binding molecules. These assays will help to rank competitive properties of EGFR inhibitors.