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Steffen Heeg Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Medical Center – University of Freiburg, Freiburg, Germany Abstract: Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities. Keywords: telomere based therapy, gastrointestinal cancer, telomere maintenance, telomerase inhibition

Intervalley excitons with electron and hole wavefunctions residing in different valleys determine the long-range transport and dynamics observed in many semiconductors. However, these excitons with vanishing oscillator strength do not directly couple to light and, hence, remain largely unstudied. Here, we develop a simple nanomechanical technique to control the energy hierarchy of valleys via their contrasting response to mechanical strain. We use our technique to discover previously inaccessible intervalley excitons associated with K, Γ, or Q valleys in prototypical 2D semiconductors WSe 2 and WS 2 . We also demonstrate a new brightening mechanism, rendering an otherwise "dark" intervalley exciton visible via strain-controlled hybridization with an intravalley exciton. Moreover, we classify various localized excitons from their distinct strain response and achieve large tuning of their energy. Overall, our valley engineering approach establishes a new way to identify intervalley excitons and control their interactions in a diverse class of 2D systems., (© 2024. The Author(s).)

Recent advancements in materials science have shed light on the potential of exploring hierarchical assemblies of molecules on surfaces, driven by both fundamental and applicative challenges. This field encompasses diverse areas including molecular storage, drug delivery, catalysis, and nanoscale chemical reactions. In this context, the utilization of nanotube templates (NTs) has emerged as promising platforms for achieving advanced one-dimensional (1D) molecular assemblies. NTs offer cylindrical, crystalline structures with high aspect ratios, capable of hosting molecules both externally and internally (Mol@NT). Furthermore, NTs possess a wide array of available diameters, providing tunability for tailored assembly. This review underscores recent breakthroughs in the field of Mol@NT. The first part focuses on the diverse panorama of structural properties in Mol@NT synthesized in the last decade. The advances in understanding encapsulation, adsorption, and ordering mechanisms are detailed. In a second part, the review highlights the physical interactions and photophysics properties of Mol@NT obtained by the confinement of molecules and nanotubes in the van der Waals distance regime. The last part of the review describes potential applicative fields of these 1D heterostructures, providing specific examples in photovoltaics, luminescent materials, and bio-imaging. A conclusion gathers current challenges and perspectives of the field to foster discussion in related communities.

Raman spectroscopy enables the non-destructive characterization of chemical composition, crystallinity, defects, or strain in countless materials. However, the Raman response of surfaces or thin films is often weak and obscured by dominant bulk signals. Here we overcome this limitation by placing a transferable porous gold membrane, (PAuM) on the surface of interest. Slot-shaped nanopores in the membrane act as plasmonic antennas and enhance the Raman response of the surface or thin film underneath. Simultaneously, the PAuM suppresses the penetration of the excitation laser into the bulk, efficiently blocking its Raman signal. Using graphene as a model surface, we show that this method increases the surface-to-bulk Raman signal ratio by three orders of magnitude. We find that 90% of the Raman enhancement occurs within the top 2.5 nm of the material, demonstrating truly surface-sensitive Raman scattering. To validate our approach, we quantify the strain in a 12.5 nm thin Silicon film and analyze the surface of a LaNiO 3 thin film. We observe a Raman mode splitting for the LaNiO 3 surface-layer, which is spectroscopic evidence that the surface structure differs from the bulk. These results validate that PAuM gives direct access to Raman signatures of thin films and surfaces., (© 2024. The Author(s).)

Purpose: In patients with peritoneal metastasis (PM) from gastric cancer (GC), chemotherapy is the treatment of choice. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are still being debated. This randomized, controlled, open-label, multicenter phase III trial (EudraCT 2006-006088-22; ClinicalTrials.gov identifier: NCT02158988) explored the impact on overall survival (OS) of HIPEC after CRS., Patients and Methods: Adult patients with GC and histologically proven PM were randomly assigned (1:1) to perioperative chemotherapy and CRS alone (CRS-A) or CRS plus HIPEC (CRS + H). HIPEC comprised mitomycin C 15 mg/m 2 and cisplatin 75 mg/m 2 in 5 L of saline perfused for 60 minutes at 42°C. The primary end point was OS; secondary endpoints included progression-free survival (PFS), other distant metastasis-free survival (MFS), and safety. Analyses followed the intention-to-treat principle., Results: Between March 2014 and June 2018, 105 patients were randomly assigned (53 patients to CRS-A and 52 patients to CRS + H). The trial stopped prematurely because of slow recruitment. In 55 patients, treatment stopped before CRS mainly due to disease progression/death. Median OS was the same for both groups (CRS + H, 14.9 [97.2% CI, 8.7 to 17.7] months v CRS-A, 14.9 [97.2% CI, 7.0 to 19.4] months; P = .1647). The PFS was 3.5 months (95% CI, 3.0 to 7.0) in the CRS-A group and 7.1 months (95% CI, 3.7 to 10.5; P = .047) in the CRS + H group. The CRS + H group showed better MFS (10.2 months [95% CI, 7.7 to 14.7] v CRS-A, 9.2 months [95% CI, 6.8 to 11.5]; P = .0286). The incidence of grade ≥3 adverse events (AEs) was similar between groups (CRS-A, 38.1% v CRS + H, 43.6%; P = .79)., Conclusion: This study showed no OS difference between CRS + H and CRS-A. PFS and MFS were significantly better in the CRS + H group, which needs further exploration. HIPEC did not increase AEs.

Introduction: In squamous cell carcinoma of the esophagus (ESCC), therapeutical options in 2nd-line treatment are scarce with immune checkpoint inhibition being the only approved one. Ramucirumab/paclitaxel is an approved 2nd-line treatment in metastatic esophagogastric adenocarcinoma. We assessed safety and efficacy of ramucirumab/paclitaxel for ESCC., Methods: This prospective, randomized, open-label, multicenter, phase II trial evaluated paclitaxel (80 mg/m2 days 1, 8, 15) plus ramucirumab (8 mg/kg days 1, 15) (investigational arm A) versus paclitaxel alone (80 mg/m2 days 1, 8, 15) (standard arm B), both q4w, in advanced/metastatic ESCC refractory or intolerant to fluoropyrimidine and platinum-based drugs. Primary endpoint was overall survival (OS) rate at 6 months., Results: From 3/2019 to 4/2021, 21/186 planned patients were included (arm A 11 patients; arm B 10 patients) in 9 German centers. Due to slow accrual, the study was terminated prematurely. OS at 6 months was 72.7% for ramucirumab/paclitaxel and 50.0% for paclitaxel. The study design did not allow statistical comparison of the arms. PFS (3.8 vs. 3.5 months), OS (12.1 vs. 9.2 months), ORR (18.2% vs. 20.0%) and DCR (54.5% vs. 60.0%) were comparable in both arms. Most common treatment-related adverse events (TRAEs) in arm A were leucopenia (54.5%), fatigue (27.3%), and peripheral sensory neuropathy (18.2%). 27.3% in arm A and 50.0% in arm B had TRAEs ≥ grade 3., Conclusion: Ramucirumab/paclitaxel shows an acceptable tolerability and numerically improved OS at 6 months. Due to the small number of patients, the current trial must be considered exploratory and more data are needed in this indication., (© 2024 S. Karger AG, Basel.)

Mechanical strain is a powerful tuning knob for excitons, Coulomb-bound electron-hole complexes dominating optical properties of two-dimensional semiconductors. While the strain response of bright free excitons is broadly understood, the behaviour of dark free excitons (long-lived excitations that generally do not couple to light due to spin and momentum conservation) or localized excitons related to defects remains mostly unexplored. Here, we study the strain behaviour of these fragile many-body states on pristine suspended WSe 2 kept at cryogenic temperatures. We find that under the application of strain, dark and localized excitons in monolayer WSe 2 -a prototypical 2D semiconductor-are brought into energetic resonance, forming a new hybrid state that inherits the properties of the constituent species. The characteristics of the hybridized state, including an order-of-magnitude enhanced light/matter coupling, avoided-crossing energy shifts, and strain tunability of many-body interactions, are all supported by first-principles calculations. The hybridized excitons reported here may play a critical role in the operation of single quantum emitters based on WSe 2 . Furthermore, the techniques we developed may be used to fingerprint unidentified excitonic states., (© 2022. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Surface-enhanced Raman spectroscopy (SERS) demands reliable, high-enhancement substrates in order to be used in different fields of application. Here we introduce freestanding porous gold membranes (PAuM) as easy-to-produce, scalable, mechanically stable, and effective SERS substrates. We fabricate large-scale sub-30 nm thick PAuM that form freestanding membranes with varying morphologies depending on the nominal gold thickness. These PAuM are mechanically stable for pressures up to more than 3 bar and exhibit surface-enhanced Raman scattering with local enhancement factors from 10 4 to 10 5 , which we demonstrate by wavelength-dependent and spatially resolved Raman measurements using graphene as a local Raman probe. Numerical simulations reveal that the enhancement arises from individual, nanoscale pores in the membrane acting as optical slot antennas. Our PAuM are mechanically stable, provide robust SERS enhancement for excitation power densities up to 10 6 W cm -2 , and may find use as a building block in SERS-based sensing applications.

Purpose: To describe doctor of physical therapy (DPT) students' perceptions following their engagement in a health promotion and wellness service-learning event (SLE) with boy scouts., Methods: A descriptive study using a sample of convenience examined engagement in an SLE with adolescents. Reflective journals summarized student experiences with the population, confidence in executing a fitness examination and motivational interviewing (MI), and anticipated challenges and benefits before and after the SLE. Journals were analyzed for themes and associated frequencies., Results: Pre-event themes included expected communication challenges, a mutually beneficial SLE, and increased competency with the population, fitness testing, and MI. Post-event themes included communication barriers not realized, unexpected challenges, and increased confidence with the population, fitness testing, and MI., Conclusion: Engaging with adolescents in SLEs provides DPT students with skills and confidence for future clinical practice. See the Digital Abstract (available: at: http://links.lww.com/PPT/A347)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Background: Both interferon beta-1b (IFN-β-1b) and interferon beta-1a (IFN-β-1a) are immunomodulators that require regular subcutaneous self-administration by patients with multiple sclerosis (MS). However, no electronic autoinjector is available for IFN-β-1a in the US., Objective: This retrospective cohort study investigated adherence to two subcutaneous disease-modifying therapies, IFN-β-1b and IFN-β-1a, during two periods (before and after the introduction of the BETACONNECT ® autoinjector for IFN-β-1b)., Patients and Methods: Data were evaluated from the MarketScan database for adults in the US with an MS diagnosis and a medical claim for subcutaneous IFN-β-1b or IFN-β-1a, either before (October 2013-September 2015) or after the introduction of BETACONNECT (October 2016-September 2018). Patient populations were propensity-score matched by demographic and clinical characteristics. Persistence was recorded, and adherence was evaluated by medication possession ratio (MPR)., Results: The study included 196 IFN-β-1b and 365 IFN-β-1a people with MS (PwMS) (pre-BETACONNECT period), and 126 IFN-β-1b and 223 IFN-β-1a PwMS (post-BETACONNECT period). In the pre-BETACONNECT period, the proportion with at least 80% MPR was higher for IFN-β-1a (90%) than for IFN-β-1b (83%), but in the post-BETACONNECT period the proportion with ≥ 80% MPR was higher for IFN-β-1b (92%) than for IFN-β-1a (86%). In the pre-BETACONNECT period, median persistence (in days) was higher for IFN-β-1a (199) than for IFN-β-1b (152), while in post-BETACONNECT period persistence was higher for IFN-β-1b (327) than for IFN-β-1a (229)., Conclusions: Following the introduction of BETACONNECT, this exploratory study suggested that PwMS taking IFN-β-1b were more adherent compared with those taking IFN-β-1a, with higher persistence, and more than 90% reached 80% MPR, a threshold commonly used to define good adherence., (© 2021. The Author(s).)

We investigate the anti-Stokes Raman scattering of single carbyne chains confined inside double-walled carbon nanotubes. Individual chains are identified using tip-enhanced Raman scattering (TERS) and heated by resonant excitation with varying laser powers. We study the temperature dependence of carbyne's Raman spectrum and quantify the laser-induced heating based on the anti-Stokes/Stokes ratio. Due to its molecular size and its large Raman cross section, carbyne holds great promise for local temperature monitoring, with potential applications ranging from nanoelectronics to biology.

In the field of phononics, periodic patterning controls vibrations and thereby the flow of heat and sound in matter. Bandgaps arising in such phononic crystals (PnCs) realize low-dissipation vibrational modes and enable applications toward mechanical qubits, efficient waveguides, and state-of-the-art sensing. Here, we combine phononics and two-dimensional materials and explore tuning of PnCs via applied mechanical pressure. To this end, we fabricate the thinnest possible PnC from monolayer graphene and simulate its vibrational properties. We find a bandgap in the megahertz regime within which we localize a defect mode with a small effective mass of 0.72 ag = 0.002 m physical . We exploit graphene's flexibility and simulate mechanical tuning of a finite size PnC. Under electrostatic pressure up to 30 kPa, we observe an upshift in frequency of the entire phononic system by ∼350%. At the same time, the defect mode stays within the bandgap and remains localized, suggesting a high-quality, dynamically tunable mechanical system.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.

Acute pancreatitis is one of the most common gastrointestinal diseases requiring acute hospitalization and its incidence is increasing. A particular challenge is the prediction and treatment of severe cases, which only affect a minority of patients, but are associated with mortality rates of up to 30 percent. In this review, we consider the diagnostic evaluation of the disease and provide an overview of current conservative and interventional treatment strategies., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m 2 ; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI -18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1.

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

We experimentally quantify the Raman scattering from individual carbyne chains confined in double-walled carbon nanotubes. We find that the resonant differential Raman cross section of confined carbyne is on the order of 10 -22 cm 2  sr -1 per atom, making it the strongest Raman scatterer ever reported.