DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.

TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.

Clinical evaluation of a novel therapeutic single-use gastroscope: a pilot feasibility study.

BACKGROUND AND STUDY AIMS: The trend toward disposable products in gastrointestinal endoscopy, including single-use endoscopes, remains undeterred, even though crucial questions of sustainability and performance have not been sufficiently studied. The first therapeutic single-use gastroscope (Ambu aScope Gastro Large) was recently approved in Europe, but clinical data to support its use is currently unavailable. We aimed to evaluate the performance of the Ambu aScope Gastro Large in routine procedures requiring a large working channel. PATIENTS AND METHODS: Between January and May 2024, consecutive patients with an indication for therapeutic gastroscope use were included prospectively. The primary aim was to assess the intraprocedural technical success rate. RESULTS: Eight gastrointestinal bleedings, two pancreatic necrosectomies, four foreign body removals, four stent implantations, and two cryoablations were performed. The technical success rate was achieved in 16 out of 19 (84%) patients. Three crossovers to standard endoscopes occurred. Clinical success was achieved in all cases where the primary aim was achieved (85%). No adverse events were reported. CONCLUSIONS: The therapeutic single-use gastroscope demonstrated feasibility in various therapeutic procedures, however, a crossover rate of 16% and an average user quality assessment score of 3.2 on the Likert scale suggest that further technical improvements of the device are necessary.

Evaluation of a single-use gastroscope in patients presenting with suspected upper gastrointestinal hemorrhage: a pilot feasibility study (One-Scope I).

BACKGROUND : Outbreaks of multidrug-resistant bacteria due to contaminated duodenoscopes and infection risks during the COVID-19 pandemic have driven the development of single-use endoscopes. The first single-use gastroscope is now available in Europe. Besides waste disposal and cost issues, the infection risk and performance remain unclear. We aimed to evaluate a single-use gastroscope in patients with signs of upper gastrointestinal bleeding. METHODS : 20 consecutive patients presenting with clinical signs of upper gastrointestinal bleeding between October and November 2022 were included in this case series. The primary aim was technical success, defined as access to the descending duodenum and adequate assessment of the upper gastrointestinal tract for the presence of a bleeding site. RESULTS : The primary aim was achieved in 19/20 patients (95 %). The bleeding site was identified in 18 patients. A therapeutic intervention was performed in six patients (two cap-mounted clips, one standard hemostatic clip, two variceal band ligations, one hemostatic powder, two adrenaline injections); technical and clinical success were achieved in all six patients. Two crossovers to a standard gastroscope occurred. CONCLUSIONS : Use of single-use gastroscopes may be feasible for patients presenting for urgent endoscopic evaluation and treatment of upper gastrointestinal bleeding.

ChatGPT makes medicine easy to swallow: an exploratory case study on simplified radiology reports.

OBJECTIVES: To assess the quality of simplified radiology reports generated with the large language model (LLM) ChatGPT and to discuss challenges and chances of ChatGPT-like LLMs for medical text simplification. METHODS: In this exploratory case study, a radiologist created three fictitious radiology reports which we simplified by prompting ChatGPT with "Explain this medical report to a child using simple language." In a questionnaire, we tasked 15 radiologists to rate the quality of the simplified radiology reports with respect to their factual correctness, completeness, and potential harm for patients. We used Likert scale analysis and inductive free-text categorization to assess the quality of the simplified reports. RESULTS: Most radiologists agreed that the simplified reports were factually correct, complete, and not potentially harmful to the patient. Nevertheless, instances of incorrect statements, missed relevant medical information, and potentially harmful passages were reported. CONCLUSION: While we see a need for further adaption to the medical field, the initial insights of this study indicate a tremendous potential in using LLMs like ChatGPT to improve patient-centered care in radiology and other medical domains. CLINICAL RELEVANCE STATEMENT: Patients have started to use ChatGPT to simplify and explain their medical reports, which is expected to affect patient-doctor interaction. This phenomenon raises several opportunities and challenges for clinical routine. KEY POINTS: • Patients have started to use ChatGPT to simplify their medical reports, but their quality was unknown. • In a questionnaire, most participating radiologists overall asserted good quality to radiology reports simplified with ChatGPT. However, they also highlighted a notable presence of errors, potentially leading patients to draw harmful conclusions. • Large language models such as ChatGPT have vast potential to enhance patient-centered care in radiology and other medical domains. To realize this potential while minimizing harm, they need supervision by medical experts and adaption to the medical field.

Lung-on-a-Chip Models of the Lung Parenchyma.

Since the publication of the first lung-on-a-chip in 2010, research has made tremendous progress in mimicking the cellular environment of healthy and diseased alveoli. As the first lung-on-a-chip products have recently reached the market, innovative solutions to even better mimic the alveolar barrier are paving the way for the next generation lung-on-chips. The original polymeric membranes made of PDMS are being replaced by hydrogel membranes made of proteins from the lung extracellular matrix, whose chemical and physical properties exceed those of the original membranes. Other aspects of the alveolar environment are replicated, such as the size of the alveoli, their three-dimensional structure, and their arrangement. By tuning the properties of this environment, the phenotype of alveolar cells can be tuned, and the functions of the air-blood barrier can be reproduced, allowing complex biological processes to be mimicked. Lung-on-a-chip technologies also provide the possibility of obtaining biological information that was not possible with conventional in vitro systems. Pulmonary edema leaking through a damaged alveolar barrier and barrier stiffening due to excessive accumulation of extracellular matrix proteins can now be reproduced. Provided that the challenges of this young technology are overcome, there is no doubt that many application areas will benefit greatly.

γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.

The aggregation of ß-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aß42 is one of several Aß peptides, all of Aß30 to Aß43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aß42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aß peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aß-like peptides, but that only the production of Aß-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aß modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aß production.

Underwater vs Conventional Endoscopic Mucosal Resection of Large Sessile or Flat Colorectal Polyps: A Prospective Randomized Controlled Trial.

BACKGROUND & AIMS: Conventional endoscopic mucosal resection (CEMR) with submucosal injection is the current standard for the resection of large, nonmalignant colorectal polyps. We investigated whether underwater endoscopic mucosal resection (UEMR) is superior to CEMR for large (20-40mm) sessile or flat colorectal polyps. METHODS: In this prospective randomized controlled study, patients with sessile or flat colorectal polyps between 20 and 40 mm in size were randomly assigned to UEMR or CEMR. The primary outcome was the recurrence rate after 6 months. Secondary outcomes included en bloc and R0 resection rates, number of resected pieces, procedure time, and adverse events. RESULTS: En bloc resection rates were 33.3% in the UEMR group and 18.4% in the CEMR group (P = .045); R0 resection rates were 32.1% and 15.8% for UEMR vs CEMR, respectively (P = .025). UEMR was performed with significantly fewer pieces compared to CEMR (2 pieces: 45.5% UEMR vs 17.7% CEMR; P = .001). The overall recurrence rate did not differ between both groups (P = .253); however, subgroup analysis showed a significant difference in favor of UEMR for lesions of >30 mm to ≤40 mm in size (P = .031). The resection time was significantly shorter in the UEMR group (8 vs 14 minutes; P < .001). Adverse events did not differ between both groups (P = .611). CONCLUSIONS: UEMR is superior to CEMR regarding en bloc resection, R0 resection, and procedure time for large colorectal lesions and shows significantly lower recurrence rates for lesions >30 mm to ≤40 mm in size. UEMR should be considered for the endoscopic resection of large colorectal polyps.

Simulation of winter wheat response to variable sowing dates and densities in a high-yielding environment.

Crop multi-model ensembles (MME) have proven to be effective in increasing the accuracy of simulations in modelling experiments. However, the ability of MME to capture crop responses to changes in sowing dates and densities has not yet been investigated. These management interventions are some of the main levers for adapting cropping systems to climate change. Here, we explore the performance of a MME of 29 wheat crop models to predict the effect of changing sowing dates and rates on yield and yield components, on two sites located in a high-yielding environment in New Zealand. The experiment was conducted for 6 years and provided 50 combinations of sowing date, sowing density and growing season. We show that the MME simulates seasonal growth of wheat well under standard sowing conditions, but fails under early sowing and high sowing rates. The comparison between observed and simulated in-season fraction of intercepted photosynthetically active radiation (FIPAR) for early sown wheat shows that the MME does not capture the decrease of crop above ground biomass during winter months due to senescence. Models need to better account for tiller competition for light, nutrients, and water during vegetative growth, and early tiller senescence and tiller mortality, which are exacerbated by early sowing, high sowing densities, and warmer winter temperatures.

Classification, outcomes, and management of misdeployed stents during EUS-guided gastroenterostomy.

BACKGROUND AND AIMS: Stent misdeployment (SM) has hindered the dissemination of EUS-guided gastroenterostomy (EUS-GE) for gastric outlet obstruction (GOO) management. We aimed to provide a classification system for SM during EUS-GE and study clinical outcomes and management accordingly. METHODS: This is a retrospective study involving 16 tertiary care centers (8 in the United States, 8 in Europe) from March 2015 to December 2020. Patients who developed SM during EUS-GE for GOO were included. We propose classifying SM into 4 types. The primary outcome was rate and severity of SM (per American Society for Gastrointestinal Endoscopy lexicon), whereas secondary outcomes were clinical outcomes and management of dislodgement according to the SM classification type, in addition to salvage management of GOO after SM. RESULTS: From 467 EUS-GEs performed for GOO during the study period, SM occurred in 46 patients (9.85%). Most SMs (73.2%) occurred during the first 13 EUS-GE cases by the performing operators. SM was graded as mild (n = 28, 60.9%), moderate (n = 11, 23.9%), severe (n = 6, 13.0%), or fatal (n = 1, 2.2%), with 5 patients (10.9%) requiring surgical intervention. Type I SM was the most common (n = 29, 63.1%), followed by type II (n = 14, 30.4%), type IV (n = 2, 4.3%), and type III (n = 1, 2.2%). Type I SM was more frequently rated as mild compared with type II SM (75.9% vs 42.9%, P = .04) despite an equivalent rate of surgical repair (10.3% vs 7.1%, P = .7). Overall, 4 patients (8.7%) required an intensive care unit stay (median, 2.5 days). The median length of stay was 4 days after SM. CONCLUSIONS: Although SM is not infrequent during EUS-GE, most are type I, mild/moderate in severity, and can be managed endoscopically with a surgical intervention rate of approximately 11%.

Clinical and technical outcomes of patients undergoing endoscopic ultrasound-guided gastroenterostomy using 20-mm vs. 15-mm lumen-apposing metal stents.

BACKGROUND: Most studies on endoscopic ultrasound (EUS)-guided gastroenterostomy (EUS-GE) for palliation of malignant gastric outlet obstruction (GOO) utilized a 15-mm lumen-apposing metal stent (LAMS). More recently, a 20-mm LAMS has become available. This study aimed to compare rates of technical and clinical success and adverse events (AEs) in patients undergoing EUS-GE using a 20-mm vs. 15-mm LAMS. METHODS: Patients who underwent EUS-GE with 15-mm or 20-mm LAMS for malignant GOO during the period from January 2018 to October 2020 were included. The primary outcome was clinical success, defined as an increase in the gastric outlet obstruction score (GOOS) by at least 1 point during follow-up. Secondary outcomes were technical success, maximum tolerated diet, re-intervention rate, and rate/severity of AEs. RESULTS: 267 patients (mean age 67 years, 43 % women) with malignant GOO from 19 centers underwent EUS-GE. Clinical success rates were similar for the 15-mm and 20-mm stents (89.2 % [95 %CI 84.2 %-94.2 %] vs. 84.1 % [77.4%-90.6 %], respectively). However, a significantly higher proportion of patients in the 20-mm group tolerated a soft solid/complete diet at the end of follow-up (91.2 % [84.4 %-95.7 %] vs. 81.2 % [73.9 %-87.2 %], P = 0.04). Overall, AEs occurred in 33 patients (12.4 % [8.4 %-16.3 %]), with similar rates for 15-mm and 20-mm stents (12.8 % [7.5 %-18.2 %] vs. 11.8 % [6 %-17.6 %]), including incidence of severe/fatal AEs (2 % [0.4 %-5.8 %] vs. 3.4 % [0.9 %-8.4 %]). CONCLUSIONS: The 20-mm and 15-mm LAMS show similar safety and efficacy for patients undergoing EUS-GE for malignant GOO. The 20-mm LAMS allows a more advanced diet and is, thus preferred for EUS-GE.

Complication risk despite preventive endoscopic measures in patients undergoing endoscopic mucosal resection of large duodenal adenomas.

BACKGROUND : Endoscopic mucosal resection (EMR) is the standard treatment of ampullary and nonampullary duodenal adenomas. EMR of large (10-29 mm) and giant (≥ 30 mm) lesions carries a risk of complications such as delayed bleeding and perforation. Prospective data on duodenal EMR are scarce. This study aimed to evaluate the efficacy of endoscopic procedures (clipping and coagulation of visible vessels) to prevent complications after EMR of large and giant lesions. METHODS : 110 patients with 118 adenomas (29 ampullary and 89 nonampullary) were included prospectively. RESULTS : 15 lesions were small (12.7 %), 68 were large (57.6 %), and 35 were giant (29.7 %). Endoscopic prevention of delayed complications was performed in 81.4 % (n = 96) of all lesions and 94.3 % (n = 33) of giant lesions. Complete resection was achieved in 111 lesions (94.1 %). Complications were 22 delayed bleedings (18.6 %), 3 intraprocedural perforations (2.5 %), 2 delayed perforations (1.7 %), and 1 stricture (0.8 %). Major complications were associated with lesions size ≥ 30 mm (28.6 % vs. 9.6 %; P = 0.02) and ampullary adenomas (27.6 % vs. 11.2 %; P = 0.07). All minor bleeding and 75 % of major bleeding episodes were treated endoscopically; 25 % of major bleedings needed radiologic embolization. Two fatal courses were observed when delayed perforation occurred after EMR of giant lesions. Residual adenoma was detected in 20.4 % at first follow-up. CONCLUSIONS : EMR of giant duodenal neoplasia carries a substantial risk of major complications and recurrences. Resection technique and prevention of delayed complications need to be improved. Further measures should be evaluated in randomized studies.

Polymicrobial infections and microbial patterns in infected nonunions - a descriptive analysis of 42 cases.

BACKGROUND: Frequencies of polymicrobial infection and pathogens evidenced in course of infected nonunion treatment are largely unknown. Therefore, this study aims at investigating microbial patterns in infected nonunions. METHODS: Surgically treated patients with long bone infected nonunion admitted between January 2010 and March 2018 were included in the study. Microbiological culture and polymerase-chain-reaction results of tissue samples of initial and follow-up revision surgeries were assessed and compared with patient and treatment characteristics. RESULTS: Forty two patients with a mean age of 53.9 ± 17.7 years were included. In six patients (14.3%) polymicrobial infection was evident. A change of pathogens evidenced in course of the treatment occurred in 21 patients (50%). In 16 patients (38.1%) previously detected bacteria could be determined by microbial testing after further revision surgery. Staphylococcus aureus was most often detected (n = 34, 30.6%), followed by Enterococcus spp. (n = 25, 22.5%) and Staphylococcus epidermidis (n = 18, 16.2%). Five Staphylococcus aureus were resistant to methicillin (MRSA). In patients without polymicrobial infection or further germ detection in course of the treatment, 86.4% of the infections were due to Staphylococcus spp.. Infections due to Streptococcus spp. and gram-negative bacteria were only present in patients with polymicrobial infection and germ-change in course of the treatment. CONCLUSION: A low rate of polymicrobial infections was evidenced in the present study. Germ-change often occurs in course of revision surgeries. Prospective studies with more sensitive diagnostic tools are necessary to elucidate the therapeutical relevance of microbiological testing results for surgical as well as medical treatment in infected nonunions.

A context-specific cardiac ß-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart.

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-ß-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-ß-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of ß-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2-5 and GATA4 in stabilized-ß-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/ß-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing ß-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/ß-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway.

Bicarbonate sensing in mouse cortical astrocytes during extracellular acid/base disturbances.

KEY POINTS: The present study suggests that the electrogenic sodium-bicarbonate cotransporter, NBCe1, supported by carbonic anhydrase II, CAII, provides an efficient mechanism of bicarbonate sensing in cortical astrocytes. This mechanism is proposed to play a major role in setting the pHi responses to extracellular acid/base challenges in astrocytes. A decrease in extracellular [HCO3- ] during isocapnic acidosis and isohydric hypocapnia, or an increase in intracellular [HCO3- ] during hypercapnic acidosis, was effectively sensed by NBCe1, which carried bicarbonate out of the cells under these conditions, and caused an acidification and sodium fall in WT astrocytes, but not in NBCe1-knockout astrocytes. Isocapnic acidosis, hypercapnic acidosis and isohydric hypocapnia evoked inward currents in NBCe1- and CAII-expressing Xenopus laevis oocytes, but not in native oocytes, suggesting that NBCe1 operates in the outwardly directed mode under these conditions consistent with our findings in astrocytes. We propose that bicarbonate sensing of astrocytes may have functional significance during extracellular acid/base disturbances in the brain, as it not only alters intracellular pH/[HCO3- ]-dependent functions of astrocytes, but also modulates the extracellular pH/[HCO3- ] in brain tissue. ABSTRACT: Extracellular acid/base status of the mammalian brain undergoes dynamic changes during many physiological and pathological events. Although intracellular pH (pHi ) of astrocytes responds to extracellular acid/base changes, the mechanisms mediating these changes have remained unresolved. We have previously shown that the electrogenic sodium-bicarbonate cotransporter, NBCe1, is a high-affinity bicarbonate carrier in cortical astrocytes. In the present study, we investigated whether NBCe1 plays a role in bicarbonate sensing in astrocytes, and in determining the pHi responses to extracellular acid/base challenges. We measured changes in intracellular H+ and Na+ in astrocytes from wild-type (WT) and from NBCe1-knockout (KO) mice, using ion-selective dyes, during isocapnic acidosis, hypercapnic acidosis and hypocapnia. We also analysed NBCe1-mediated membrane currents in Xenopus laevis oocytes under similar conditions. Comparing WT and NBCe1-KO astrocytes, we could dissect the contribution of NBCe1, of diffusion of CO2 across the cell membrane and, after blocking carbonic anhydrase (CA) activity with ethoxyzolamide, of the role of CA, for the amplitude and rate of acid/base fluxes. Our results suggest that NBCe1 transport activity in astrocytes, supported by CA activity, renders astrocytes bicarbonate sensors in the mouse cortex. NBCe1 carried bicarbonate into and out of the cell by sensing the variations of transmembrane [HCO3- ], irrespective of the changes in intra- and extracellular pH, and played a major role in setting pHi responses to the extracellular acid/base challenges. We propose that bicarbonate sensing of astrocytes may have potential functional significance during extracellular acid/base alterations in the brain.

Proton Fall or Bicarbonate Rise: GLYCOLYTIC RATE IN MOUSE ASTROCYTES IS PAVED BY INTRACELLULAR ALKALINIZATION.

Glycolysis is the primary step for major energy production in the cell. There is strong evidence suggesting that glucose consumption and rate of glycolysis are highly modulated by cytosolic pH/[H(+)], but those can also be stimulated by an increase in the intracellular [HCO3 (-)]. Because proton and bicarbonate shift concomitantly, it remained unclear whether enhanced glucose consumption and glycolytic rate were mediated by the changes in intracellular [H(+)] or [HCO3 (-)]. We have asked whether glucose metabolism is enhanced by either a fall in intracellular [H(+)] or a rise in intracellular [HCO3 (-)], or by both, in mammalian astrocytes. We have recorded intracellular glucose in mouse astrocytes using a FRET-based nanosensor, while imposing different intracellular [H(+)] and [CO2]/[HCO3 (-)]. Glucose consumption and glycolytic rate were augmented by a fall in intracellular [H(+)], irrespective of a concomitant rise or fall in intracellular [HCO3 (-)]. Transport of HCO3 (-) into and out of astrocytes by the electrogenic sodium bicarbonate cotransporter (NBCe1) played a crucial role in causing changes in intracellular pH and [HCO3 (-)], but was not obligatory for the pH-dependent changes in glucose metabolism. Our results clearly show that it is the cytosolic pH that modulates glucose metabolism in cortical astrocytes, and possibly also in other cell types.

High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a (177)Lu-based CD22-specific radioimmunoconjugate and rituximab.

PURPOSE: Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy ß-emitter (177)Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. METHODS: The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of (177)Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 (null) ) interleukin-2 receptor common gamma chain (IL2rγ (null) ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. (177)Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. RESULTS: Conjugation of CHX-A"-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the (177)Lu-labelled anti-CD22 IgG than of (177)Lu-labelled rituximab. Treatment with (177)Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with (177)Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. CONCLUSION: These findings suggest that dual targeting with (177)Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

Giant Cross Section for Molecular Ion Formation in Ultracold Rydberg Gases.

We have studied the associative ionization of a Rydberg atom and a ground-state atom in an ultracold Rydberg gas. The measured scattering cross section is 3 orders of magnitude larger than the geometrical size of the produced molecule. This giant enhancement of the reaction kinetics is due to an efficient directed mass transport which is accelerated by the Rydberg electron. We also find that the total inelastic scattering cross section is given by the geometrical size of the Rydberg electron's wave function.

Muscular forces affect the glycosaminoglycan content of joint cartilage: unloading in human volunteers with the HEPHAISTOS lower leg orthosis.

BACKGROUND AND PURPOSE: Unloading alters the thickness of joint cartilage. It is unknown, however, to what extent unloading leads to a loss of glycosaminoglycans (GAGs) in the cartilage tissue. We hypothesized that muscle forces, in addition to axial loading, are necessary to maintain the joint cartilage GAG content of the knee and the upper and lower ankle. PATIENTS AND METHODS: The HEPHAISTOS orthosis was worn unilaterally by 11 men (mean age 31 (23-50) years old) for 56 days. The orthosis reduces activation and force production of the calf muscles while it permits full gravitational loading of the lower leg. MRI measurements of the knee and ankle were taken before the intervention, during the intervention (on day 49), and 14 days after the end of the intervention. Cartilage segmentation was conducted semiautomatically for the knee joint (4 segments) and for the upper (tibio-talar) and lower (subtalar) ankle joints (2 segments each). Linear mixed-effects (LME) models were used for statistical analysis. RESULTS: 8 volunteers completed the MRI experiment. In the lower ankle joint, differences in ΔT1 were found between the end of the intervention and 14 days after (p = 0.004), indicating a decrease in GAG content after reloading. There were no statistically significant differences in ΔT1 values in the knee and upper ankle joints. INTERPRETATION: Our findings suggest that in addition to gravitational load, muscular forces affect cartilage composition depending on the local distribution of forces in the joints affected by muscle contraction.

Systematic review of the effectiveness of standalone passive countermeasures on microgravity-induced physiologic deconditioning.

A systematic review of literature was conducted to evaluate the effectiveness of passive countermeasures in ameliorating the cardiopulmonary and musculoskeletal effects of gravitational unloading on humans during spaceflight. This systematic review is the third of a series being conducted by the European Space Agency to evaluate the effectiveness of countermeasures to physiologic deconditioning during spaceflight. With future long-duration space missions on the horizon, it is critical to understand the effectiveness of existing countermeasures to promote astronaut health and improve the probability of future mission success. An updated search for studies examining passive countermeasures was conducted in 2021 to supplement results from a broader search conducted in 2017 for all countermeasures. Ground-based analogue and spaceflight studies were included in the search. A total of 647 articles were screened following removal of duplicates, of which 16 were included in this review. Data extraction and analysis, quality assessment of studies, and transferability of reviewed studies to actual spaceflight based on their bed-rest protocol were conducted using dedicated tools created by the Aerospace Medicine Systematic Review Group. Of the 180 examined outcomes across the reviewed studies, only 20 were shown to have a significant positive effect in favour of the intervention group. Lower body negative pressure was seen to significantly maintain orthostatic tolerance (OT) closer to baseline as comparted to control groups. It also was seen to have mixed efficacy with regards to maintaining resting heart rate close to pre-bed rest values. Whole body vibration significantly maintained many balance-related outcome measures close to pre-bed rest values as compared to control. Skin surface cooling and centrifugation both showed efficacy in maintaining OT. Centrifugation also was seen to have mixed efficacy with regards to maintaining VO2max close to pre-bed rest values. Overall, standalone passive countermeasures showed no significant effect in maintaining 159 unique outcome measures close to their pre-bed rest values as compared to control groups. Risk of bias was rated high or unclear in all studies due to poorly detailed methodologies, poor control of confounding variables, and other sources of bias (i.e. inequitable recruitment of participants leading to a higher male:female ratios). The bed-rest transferability (BR) score varied from 2-7, with a median score of 5. Generally, most studies had good BR transferability but underreported on factors such as control of sunlight or radiation exposure, diet, level of exercise and sleep-cycles. We conclude that: (1) Lack of standardisation of outcome measurement and methodologies has led to large heterogeneity amongst studies; (2) Scarcity of literature and high risk of bias amongst existing studies limits the statistical power of results; and (3) Passive countermeasures have little or no efficacy as standalone measures against cardiopulmonary and musculoskeletal deconditioning induced by spaceflight related to physiologic deterioration due to gravity un-loading.