Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2(+) γδ T cell cytotoxicity in a perforin-dependent manner.

Vδ2(+) T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2(+) T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2(+) T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2(+) T cell cytotoxicity. Vδ2(+) T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2(+) T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy

Spatiotemporal Communication in Artificial Cell Consortia for Dynamic Control of DNA Nanostructures

[EN] The spatiotemporal orchestration of cellular processes is a ubiquitous phenomenon in pluricellular organisms and bacterial communities, where sender cells secrete chemical signals that activate specific pathways in distant receivers. Despite its importance, the engineering and investigation of spatiotemporal communication in artificial cell consortia remains underexplored. In this study, we present spatiotemporal communication between cellular-scale entities acting as both senders and receivers. The transmitted signals are leveraged to elicit conformational alterations within compartmentalized DNA structures. Specifically, sender entities control and generate diffusive chemical signals, namely, variations in pH, through the conversion of biomolecular inputs. In the receiver population, compartmentalized DNA nanostructures exhibit changes in conformation, transitioning between triplex and duplex assemblies, in response to this pH variation. We demonstrate the temporal regulation of activated DNA nanostructures through the coordinated action of two antagonistic sender populations. Furthermore, we illustrate the transient distance-dependent activation of the receivers, facilitated by sender populations situated at defined spatial locations. Collectively, our findings provide novel avenues for the design of artificial cell consortia endowed with programmable spatiotemporal dynamics through chemical communication.The authors would like to acknowledge the support from the Dutch Ministry of Education, Culture, and Science (Gravitation programs 024.001.035, 024.003.013, 024.005.020 - Interactive Polymer Materials IPM, and the Spinoza premium), ERC Advanced Grant (Artisym 694120), ERC Advanced Grant Edison (101052997), the Spanish Ministry of Science and Innovation, AEI, and FEDER-EU (project PID2021-126304OB-C41), and the GVA (Project CIPROM/2021/007). A.L.-L. acknowledges support from the MSCA Cofund project oLife, which has received funding from the European Union's Horizon 2020 research and innovation program under the Grant Agreement 847675. A.L.-L. thanks the Spanish Government for his "Ramon y Cajal" Fellowship (RYC2021-034728-I), funded by MCIN/AEI/10.13039/501100011033 and by the European Union >/>. A.L-L. also thanks the UPV for funding (Ayuda para potenciar la investigacion postdoctoral de la UPV (PAID-PD-22), Ayuda a Primeros Proyectos de Investigacion (PAID-06-22), Vicerrectorado de Investigacion de la Universitat Politecnica de Valencia (UPV)).Llopis-Lorente, A.; Shao, J.; Ventura-Cobos, J.; Buddingh, BC.; Martínez-Máñez, R.; Van Hest, JCM.; Abdelmohsen, LKEA. (2024). Spatiotemporal Communication in Artificial Cell Consortia for Dynamic Control of DNA Nanostructures. ACS CENTRAL SCIENCE. 10(8):1619-1628. https://doi.org/10.1021/acscentsci.4c007021619162810

Limited diagnostic accuracy and clinical impact of single-operator peroral cholangioscopy for indeterminate biliary strictures

BACKGROUND: Single-operator peroral cholangioscopy (sPOCS) is considered a valuable diagnostic modality for indeterminate biliary strictures. Nevertheless, studies show large variation in its characteristics and measures of diagnostic accuracy. Our aim was to estimate the diagnostic accuracy of sPOCS visual assessment and targeted biopsies for indeterminate biliary strictures. Additional aims were: estimation of the clinical impact of sPOCS and comparison of diagnostic accuracy with brush cytology. METHODS: A retrospective single-center study of adult patients who underwent sPOCS for indeterminate biliary strictures was performed. Diagnostic accuracy was defined as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The clinical impact of sPOCS was assessed by review of medical records, and classified according to its influence on patient management. RESULTS: 80 patients were included, with 40 % having primary sclerosing cholangitis (PSC). Prior ERCP was performed in 88 %, with removal of a biliary stent prior to sPOCS in 55 %. The sensitivity, specificity, PPV, and NPV for sPOCS visual impression and targeted biopsies were 64 %, 62 %, 41 %, and 84 %, and 15 %, 65 %, 75 %, and 69 %, respectively. The clinical impact of sPOCS was limited; outcome changed management in 17 % of patients. Sequential brush cytology sensitivity, specificity, PPV, and NPV were 47 %, 95 %, 80 %, and 83 %. CONCLUSIONS: The diagnostic accuracy of sPOCS for indeterminate biliary strictures was found to be inferior to brush cytology, with a low impact on patient management. These findings are obtained from a select patient population with a high prevalence of PSC and plastic stents in situ prior to sPOCS

Intact interferon signaling in peripheral blood leukocytes of high-grade osteosarcoma patients

High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional. We studied the molecular and functional effects of interferon treatment on peripheral blood lymphocytes and monocytes of osteosarcoma patients, both in vivo and ex vivo. In contrast to other tumor types, in osteosarcoma, interferon signaling as determined by the phosphorylation of signal transducer and activator of transcription (STAT)1 at residue 701 was intact in immune cell subsets of 33 osteosarcoma patients as compared to 19 healthy controls. Also, cytolytic activity of interferon-α stimulated natural killer cells against allogeneic (n = 7 patients) and autologous target cells (n = 3 patients) was not impaired. Longitudinal monitoring of three osteosarcoma patients on interferon-α monotherapy revealed a relative increase in the CD16-positive subpopulation of monocytes during treatment. Since interferon signaling is intact in immune cells of osteosarcoma patients, there is a potential for indirect immunological effects of interferon-α treatment in osteosarcoma

Abdominal Compartment Syndrome and Intra-abdominal Ischemia in Patients with Severe Acute Pancreatitis

Severe acute pancreatitis may be complicated by intra-abdominal hypertension (IAH), abdominal compartment syndrome (ACS), and intestinal ischemia. The aim of this retrospective study is to describe the incidence, treatment, and outcome of patients with severe acute pancreatitis and ACS, in particular the occurrence of intestinal ischemia. The medical records of all patients admitted with severe acute pancreatitis admitted to the ICU of a tertiary referral center were reviewed. The criteria proposed by the World Society of the Abdominal Compartment Syndrome (WSACS) were used to determine whether patients had IAH or ACS. Fifty-nine patients with severe acute pancreatitis were identified. Intra-abdominal pressure (IAP) measurements were performed in 29 patients (49.2 %). IAH was present in all patients (29/29). ACS developed in 13/29 (44.8 %) patients. Ten patients with ACS underwent decompressive laparotomy. A large proportion of patients with ACS had intra-abdominal ischemia upon laparotomy: 8/13 (61.5 %). Mortality was high in both the ACS group and the IAH group. This study confirms that ACS is common in severe acute pancreatitis. Intra-abdominal ischemia occurs in a large proportion of patients with ACS. Swift surgical intervention may be indicated when conservative measures fail in patients with ACS. National and international guidelines need to be updated so that routine IAP measurements become standard of care for patients with severe acute pancreatitis in the ICU

Een zuigeling met een gecompliceerde navelontsteking

Een geïnfecteerde navel (omfalitis) is een veelvoorkomende aandoening in de neonatale periode. Meestal gaat het om een onschuldige oppervlakkige huidontsteking. In zeldzame gevallen heeft een omfalitis een gecompliceerd beloop, zoals wij laten zien in dit artikel. Ziektegeschiedenis Een à terme geboren jongen van 20 dagen oud werd door de huisarts naar de kinderarts verwezen vanwege koorts (maximale temperatuur: 38,3 °C) en een rode, nattende navel

Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture

Background: In vitro expanded mesenchymal stromal cells (MSCs) are increasingly used as experimental cellular therapy. However, there have been concerns regarding the safety of their use, particularly with regard to possible oncogenic transformation. MSCs are the hypothesized precursor cells of high-grade osteosarcoma, a tumor with often complex karyotypes occurring mainly in adolescents and young adults.Methods: To determine if MSCs from osteosarcoma patients could be predisposed to malignant transformation we cultured MSCs of nine osteosarcoma patients and five healthy donors for an average of 649 days (range 601679 days). Also, we compared MSCs derived from osteosarcoma patients at diagnosis and from healthy donors using genome wide gene expression profiling.Results: Upon increasing passage, increasing frequencies of binucleate cells were detected, but no increase in proliferation suggestive of malignant transformation occurred in MSCs from either patients or donors. Hematopoietic cell specific Lyn substrate 1 (HLCS1) was differentially expressed (fold change 0.25, P value 0.0005) between MSCs of osteosarcoma patients (n = 14) and healthy donors (n = 9).Conclusions: This study shows that although HCLS1 expression was downregulated in MSCs of osteosarcoma patients and binucleate cells were present in both patient and donor derived MSCs, there was no evidence of neoplastic changes to occur during long-term culture

Safety Measures During Cholecystectomy: Results of a Nationwide Survey

BACKGROUND: This study aimed to identify safety measures practiced by Dutch surgeons during laparoscopic cholecystectomy. METHOD: An electronic questionnaire was sent to all members of the Dutch Society of Surgery with a registered e-mail address. RESULTS: The response rate was 40.4% and 453 responses were analyzed. The distribution of the respondents with regard to type of hospital was similar to that in the general population of Dutch surgeons. The critical view of safety (CVS) technique is used by 97.6% of the surgeons. It is documented by 92.6%, mostly in the operation report (80.0%), but often augmented by photography (42.7%) or video (30.2%). If the CVS is not obtained, 50.9% of surgeons convert to the open approach, 39.1% continue laparoscopically, and 10.0% perform additional imaging studies. Of Dutch surgeons, 53.2% never perform intraoperative cholangiography (IOC), 41.3% perform it incidentally, and only 2.6% perform it routinely. A total of 105 bile duct injuries (BDIs) were reported in 14,387 cholecystectomies (0.73%). The self-reported major BDI rate (involving the common bile duct) was 0.13%, but these figures need to be confirmed in other studies. CONCLUSION: The CVS approach in laparoscopic cholecystectomy is embraced by virtually all Dutch surgeons. The course of action when CVS is not obtained varies. IOC seems to be an endangered skill as over half the Dutch surgeons never perform it and the rest perform it only incidentally