Narratives of contingency and practices of comparing in the emergence of German molecular genetics (1958-1968).

This article explores the emergence of molecular approaches in German genetic research during the 1958-1968 decade as a period of contingency and alternative possibilities. We introduce "Narratives of Contingency" as an analytical framework to examine how scientists construct a specific narrative - linking past experiences with expectations of future conditions - in order to outline and navigate pathway-decisions in the present. We apply this framework to Hans-Jörg Rheinberger's developmental model of molecular genetics and illustrate how the stages he identifies - the direction of the field, institutional developments, and epistemological demarcations - were already central themes in the comparative practices underlying narratives of contingency in this early period. Narratives of contingency can thus serve as a systematic framework for analyzing the processes through which new scientific fields, institutions, and epistemic horizons emerge, and possibly also for identifying historically plausible fork moments or alternative pathways not taken.

Experimental Demonstration of Surface Plasmon Polaritons Reflection and Transmission Effects.

Special integrated photonic surface structures composed of a dielectric semicircle ridge and a dielectric block placed on a metal substrate are proposed for the investigation of surface plasmon polariton (SPP) reflection and transmission effects. A fabrication method called microscope projection photolithography was employed for the preparation of the structures. Leakage radiation microscopy was applied for the excitation and observation of surface plasmon polaritons (SPPs). It was observed that SPPs exhibit a remarkable decrease in intensity when impinging onto the rectangular dielectric block. Nevertheless, the transmitted wave out of the dielectric block was always observable. The propagation behavior of both the reflected waves at two boundaries (air/dielectric and dielectric/air) and the transmitted wave inside the dielectric block were demonstrated for different SPP incident conditions. The variation of the angles of reflection and transmission with respect to the incident angle was analytically and experimentally investigated. An agreement between the calculated results and the experimental results was obtained. Our findings might allow for novel applications in sensing and analytics once the structures will be functionalized.

The Interaction of Guest Molecules with Co-MOF-74: A Vis/NIR and Raman Approach.

Co-MOF-74 rod like crystals with a length of several hundred micrometers are synthesized by a solvothermal procedure and their interaction with different gases is evaluated for selective gas sensing. We show strongly anisotropic absorption behavior of the Co-MOF-74 crystals when illuminated with polarized light. The interactions of guests (CO2 , propane, propene, Ar, MeOH, H2 O) with Co-MOF-74, is studied by various spectroscopic techniques. Vis/NIR shows peak shifts of Co-MOF-74 depending on the interaction with the guest. In the visible and the NIR the maximum absorbance is shifted selectively corresponding to the intensity of the CoII -guest interaction. Even propene and propane could be distinguished at room temperature by their different interactions with Co-MOF-74. Raman spectroscopy was used to detect a modified vibrational behavior of Co-MOF-74 upon gas adsorption. We show that the adsorption of H2 O leads to a characteristic shift of the peak maxima in the Raman spectra.

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. METHODS: The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 µg), with one dose of cyclophosphamide (300 mg/m2) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. FINDINGS: Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the groups (33·17 months [95% CI 27·81-41·36] in the sunitinib plus IMA901 group vs not reached [33·67-not reached] in the sunitinib monotherapy group; hazard ratio 1·34 [0·96-1·86]; p=0·087). 116 (57%) of 202 patients in the sunitinib plus IMA901 group and 62 (47%) of 132 in the sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse [possibly related to sunitinib], one oesophageal varices haemorrhage [possibly related to sunitinib], one cardiac arrest [possibly related to sunitinib], and one myocardial infarction) and eight (6%) patients in the sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident [possibly treatment related], and sepsis). INTERPRETATION: IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. FUNDING: Immatics Biotechnologies.

All-polymer arrayed waveguide grating at 850 nm: design, fabrication, and characterization.

In this Letter, a novel all-polymer arrayed waveguide grating (AWG) device with an operating wavelength around 850 nm is reported. The all-polymer AWG consists of polymer ridge waveguides fabricated on a thin poly(methyl methacrylate) foil via microscope projection photolithography. The developed device is suitable to be integrated into optical circuits, e.g., a planar polymer foil and, along with other optical integrated devices, to be used for different sensing applications. The functionality of the device is demonstrated by using a fiber Bragg grating sensor and performing strain measurements.

Cascaded-focus laser writing of low-loss waveguides in polymers.

Waveguide writing in poly (methyl methacrylate) (PMMA) with femtosecond laser radiation is presented. An adequate refractive index change is induced in the border area below the irradiated focal volume. It supports an almost symmetric fundamental mode with propagation losses down to 0.5 dB/cm, the lowest losses observed so far in this class of materials. The writing process with a cascaded focus is demonstrated to be highly reliable over a large parameter range.

Ultrafast surface plasmon-polariton logic gates and half-adder.

In this paper, we present a plasmonic model system for the realization of ultrafast all-optical NOT, AND, OR, and XOR gate operations using linear interference effects in dielectric crossed waveguide structures. The waveguides for the surface plasmon-polaritons are produced by a simple but highly accurate microscopic lithographic process and are optimized for single mode operation at an excitation laser wavelength of 800 nm. The functionality of the presented structures is demonstrated using sub-30 fs laser pulses from a mode locked titanium:sapphire laser. Using leakage radiation microscopy we show ultrafast SPP switching and logic operations of one basic structure consisting of two crossed waveguides with an additional output waveguide along the bisecting line of the input waveguides. The individual gates are realized on a footprint of 10 µm × 20 µm. Experimental investigations are supported by finite-difference time-domain simulations, where good agreement between experimental results and numerical simulations is obtained. To exploit the high precision of the fabrication method and its huge potential for realizing functional complex plasmonic circuitry we experimentally demonstrate a half-adder structure and its operation by combining and cascading several plasmonic waveguide components and logic gate elements on an area of only 10 µm × 28 µm.

The interplay between localized and propagating plasmonic excitations tracked in space and time.

In this work, the mutual coupling and coherent interaction of propagating and localized surface plasmons within a model-type plasmonic assembly is experimentally demonstrated, imaged, and analyzed. Using interferometric time-resolved photoemission electron microscopy the interplay between ultrashort surface plasmon polariton wave packets and plasmonic nanoantennas is monitored on subfemtosecond time scales. The data reveal real-time insights into dispersion and localization of electromagnetic fields as governed by the elementary modes determining the functionality of plasmonic operation units.

Spatiotemporal characterization of SPP pulse propagation in two-dimensional plasmonic focusing devices.

The spatiotemporal evolution of a SPP wave packet with femtosecond duration is experimentally investigated in two different plasmonic focusing structures. A two-dimensional reconstruction of the plasmonic field in space and time is possible by the numerical analysis of interferometric time-resolved photoemission electron microscopy data. We show that the time-integrated and time-resolved view onto the wave packet dynamics allow one to characterize and compare the capabilities of two-dimensional components for use in plasmonic devices operating with ultrafast pulses.

Nanostripe length dependence of plasmon-induced material deformations.

Following the impact of a single femtosecond light pulse on nickel nanostripes, material deformations-or "nanobumps"-are created. We have studied the dependence of these nanobumps on the length of nanostripes and verified the link with plasmons. More specifically, local electric currents can melt the nanostructures in the hotspots, where hydrodynamic processes give rise to nanobumps. This process is further confirmed by independently simulating local magnetic fields, since these are produced by the same local electric currents.

Near-field mapping of plasmonic antennas by multiphoton absorption in poly(methyl methacrylate).

Mapping the optical near-field response around nanoantennas is a challenging yet indispensable task to engineer light-matter interaction at the nanometer scale. Recently, photosensitive molecular probes, which undergo morphological or chemical changes induced by the local optical response of the nanostructures, have been proposed as a handy alternative to more cumbersome optical and electron-based techniques. Here, we report four-photon absorption in poly(methyl methacrylate) (PMMA) as a very promising tool for nanoimaging the optical near-field around nanostructures over a broad range of near-infrared optical wavelengths. The high performance of our approach is demonstrated on single-rod antennas and coupled gap antennas by comparing experimental maps with 3D numerical simulations of the electric near-field intensity.

Demonstration of magnetic dipole resonances of dielectric nanospheres in the visible region.

Strong resonant light scattering by individual spherical Si nanoparticles is experimentally demonstrated, revealing pronounced resonances associated with the excitation of magnetic and electric modes in these nanoparticles. It is shown that the low-frequency resonance corresponds to the magnetic dipole excitation. Due to high permittivity, the magnetic dipole resonance is observed in the visible spectral range for Si nanoparticles with diameters of ∼200 nm, thereby opening a way to the realization of isotropic optical metamaterials with strong magnetic responses in the visible region.

Feasibility and Safety of Personalized, Multi-Target, Adoptive Cell Therapy (IMA101): First-in-Human Clinical Trial in Patients with Advanced Metastatic Cancer.

IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose IL2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n = 6; Grade 2, n = 4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in posttreatment tumor tissue. Individual T-cell receptors (TCR) contained in T-cell products exhibited broad variation in TCR avidity, with the majority being low avidity. High-avidity TCRs were identified in some patients' products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs. See related Spotlight by Uslu and June, p. 865.

Closely packed hexagonal conical microlens array fabricated by direct laser photopolymerization.

We apply femtosecond laser direct writing in photopolymers for manufacturing of conical microlenses and closely packed arrays thereof. We demonstrate the fabrication of high optical quality axicons of 15 µm in radius, having 150°, 160°, and 170° cone angles. Their optical properties and performance are modeled using the finite-difference time-domain method and compared with experimentally measured data. Additionally, optimization of the laser direct writing parameters regarding these types of micro-objects is presented. Possible applications of closely packed arrays of axicon microlenses are discussed, having potential attractivity in the fields of modern microscopy, light-based material processing, particle manipulation in microfluidic, and optofluidic applications.

Quantitative immunopeptidomics reveals a tumor stroma-specific target for T cell therapy.

T cell receptor (TCR)-based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide-human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.

Phase I/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma.

PURPOSE: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. PATIENTS AND METHODS: A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. RESULTS: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. CONCLUSIONS: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.

Photonic bandgap plasmonic waveguides.

A type of a plasmonic waveguide has been proposed featuring an "open" design that is easy to manufacture, simple to excite and offers convenient access to a plasmonic mode. Optical properties of photonic bandgap (PBG) plasmonic waveguides are investigated experimentally by leakage radiation microscopy and numerically using the finite element method confirming photonic bandgap guidance in a broad spectral range. Propagation and localization characteristics of a PBG plasmonic waveguide have been discussed as a function of the wavelength of operation, waveguide core size, and the number of ridges in the periodic reflector for fundamental and higher order plasmonic modes of the waveguide.

UV-LED projection photolithography for high-resolution functional photonic components.

The advancement of micro- and nanostructuring techniques in optics is driven by the demand for continuous miniaturization and the high geometrical accuracy of photonic devices and integrated systems. Here, UV-LED projection photolithography is demonstrated as a simple and low-cost approach for rapid generation of two-dimensional optical micro- and nanostructures with high resolution and accuracy using standard optics only. The developed system enables the projection of structure patterns onto a substrate with 1000-fold demagnification. Photonic devices, e.g., waveguides and microring resonators, on rigid or flexible substrates with varied geometrical complexity and overall structure dimensions from the nanometer to centimeter scale were successfully prepared. In particular, high-resolution gratings with feature sizes down to 150 nm and periods as small as 400 nm were realized for the first time by this approach. Waveguides made of doped laser active materials were fabricated, and their spontaneous emission was detected. The demonstrated superior performance of the developed approach may find wide applications in photonics, plasmonics, and optical materials science, among others.

Phase II study of the human anti-epithelial cell adhesion molecule antibody adecatumumab in prostate cancer patients with increasing serum levels of prostate-specific antigen after radical prostatectomy.

BACKGROUND: Rising serum levels of prostate-specific antigen (PSA) after radical prostatectomy are indicative of recurrent prostate cancer. This double-blind, placebo-controlled phase II study evaluated the anti-tumour activity of the anti-epithelial cell adhesion molecule (EpCAM) antibody adecatumumab in delaying biochemical disease progression. PATIENTS AND METHODS: Prostate cancer patients with increasing serum PSA levels following radical prostatectomy were randomized to low- (2 mg/kg) or high-dose adecatumumab (6 mg/kg) or placebo. The primary efficacy endpoint was the mean change from baseline in total serum PSA at week 24. Secondary endpoints included PSA response rate, prolongation of serum PSA doubling time and time to biochemical disease progression. RESULTS: The primary and secondary endpoints of the study were not met in the predefined analyses. In a retrospective analysis of patients with baseline PSA ≤ 1 ng/ml and a high EpCAM expression, both the mean increase in PSA from baseline to week 24 and the PSA doubling time at week 15 were significantly improved in the high-dose adecatumumab group compared with the placebo group. Most frequent treatment-related clinical adverse events were gastrointestinal (diarrhoea and nausea) or general events (chills), showing a dose dependency but no grade 3/4 intensity in any patient. CONCLUSION: In men with rising PSA levels after radical prostatectomy and no evidence of clinical relapse, adecatumumab delayed disease progression in a subgroup of patients with baseline PSA levels ≤ 1 ng/ml and high EpCAM-expressing tumours.

Nanofabrication of High-Resolution Periodic Structures with a Gap Size Below 100 nm by Two-Photon Polymerization.

In this paper, approaches for the realization of high-resolution periodic structures with gap sizes at sub-100 nm scale by two-photon polymerization (2PP) are presented. The impact of laser intensity on the feature sizes and surface quality is investigated. The influence of different photosensitive materials on the structure formation is compared. Based on the elliptical geometry character of the voxel, the authors present an idea to realize high-resolution structures with feature sizes less than 100 nm by controlling the laser focus position with respect to the glass substrate. This investigation covers structures fabricated respectively in the plane along and perpendicular to the major axis of voxel. The authors also provide a useful approach to manage the fabrication of proposed periodic structure with a periodic distance of 200 nm and a gap size of 65 nm.