Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most ...abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin.Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC
) value for anti-CSP mAbs (IC
2A10: 24 nM, IC
3SP2: 71 nM). We found a sevenfold discrepancy between the IC
and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development.
Malaria vaccine candidates based on live, attenuated sporozoites have led to high levels of protection. However, their efficacy critically depends on the sporozoites' ability to reach and infect the ...host liver. Administration via mosquito inoculation is by far the most potent method for inducing immunity but highly impractical. Here, we observed that intradermal syringe-injected
sporozoites (
SPZ) were 3-fold less efficient in migrating to and infecting mouse liver than mosquito-inoculated sporozoites (
SPZ). This was related to a clustered dermal distribution (2-fold-decreased median distance between
SPZ and
SPZ) and, more importantly, a 1.4-fold (significantly)-slower and more erratic movement pattern. These erratic movement patterns were likely caused by alteration of dermal tissue morphology (>15-μm intercellular gaps) due to injection of fluid and may critically decrease sporozoite infectivity. These results suggest that novel microvolume-based administration technologies hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.
Malaria still causes a major burden on global health and the economy. The efficacy of live, attenuated malaria sporozoites as vaccine candidates critically depends on their ability to migrate to and infect the host liver. This work sheds light on the effect of different administration routes on sporozoite migration. We show that the delivery of sporozoites via mosquito inoculation is more efficient than syringe injection; however, this route of administration is highly impractical for vaccine purposes. Using confocal microscopy and automated imaging software, we demonstrate that syringe-injected sporozoites do cluster, move more slowly, and display more erratic movement due to alterations in tissue morphology. These findings indicate that microneedle-based engineering solutions hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.
Dendrimers are well‐defined hyperbranched macromolecules with characteristic globular structures for the larger systems. These novel polymers have inspired many chemists to develop new materials and ...several applications have been explored, catalysis being one of them. The recent impressive strides in synthetic procedures increased the accessibility of functionalized dendrimers, resulting in a rapid development of dendrimer chemistry. The position of the catalytic site(s) as well as the spatial separation of the catalysts appears to be of crucial importance. Dendrimers that are functionalized with transition metals in the core potentially can mimic the properties of enzymes, their efficient natural counterparts, whereas the surface‐functionalized systems have been proposed to fill the gap between homogeneous and heterogeneous catalysis. This might yield superior catalysts with novel properties, that is, special reactivity or stability. Both the core and periphery strategies lead to catalysts that are sufficiently larger than most substrates and products, thus separation by modern membrane separation techniques can be applied. These novel homogeneous catalysts can be used in continuous membrane reactors, which will have major advantages particularly for reactions that benefit from low substrate concentrations or suffer from side reactions of the product. Here we review the recent progress and breakthroughs made with these promising novel transition metal functionalized dendrimers that are used as catalysts, and we will discuss the architectural concepts that have been applied.
The advantages of homogenous and heterogeneous catalysts can be combined by using transition metal functionalized dendrimers. Periphery‐functionalized dendimers (left) will promote cooperative effects between the metal centers, whereas core‐functionalized dendrimers (right) can profit from site‐isolation effects and be used as enzyme mimics. Both systems are generally much larger than the substrates and products, thus providing an intrinsic solution to the problem of separating homogeneous catalysts. In the last decade considerable progress has been made in the development of novel dendritic catalysts. In this review the different concepts and progress in transition metal dendritic catalysis will be discussed.
Arthroplasty surgery of the knee and hip is performed in two to three million patients annually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiotics, and implant ...retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria-specific hybrid tracer (
Tc-UBI
-Cy5) and its ability to visualize the bacterial load on femoral implants using clinical-grade image guidance methods.
Tc-UBI
-Cy5 specificity for
was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of
cultured on femoral prostheses using fluorescence imaging and freehand single photon emission CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria.
Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be complemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were identified using imaging, which included 500 to 2,000 viable bacteria.
The hybrid tracer
Tc-UBI
-Cy5 allowed effective bacterial staining. Qualitative real-time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies.Cite this article:
2023;12(1):72-79.
AimsData from patient registries give insight into the management of patients with heart failure (HF), but actual data from unselected real-world HF patients are scarce. Therefore, we performed a ...cross sectional study of current HF care in the period 2013–2016 among more than 10,000 unselected HF patients at HF outpatient clinics in the Netherlands.MethodsIn 34 participating centres, all 10,910 patients with chronic HF treated at cardiology centres were included in the CHECK-HF registry. Of these, most (96%) were managed at a specific HF outpatient clinic. Heart failure was typically diagnosed according to the ESC guidelines 2012, based on signs, symptoms and structural and/or functional cardiac abnormalities. Information on diagnostics, treatment and co-morbidities were recorded, with specific focus on drug therapy and devices. In our cohort, the mean age was 73 years (SD 12) and 60% were male. Frequent co-morbidities reported in the patient records were diabetes mellitus 30%, hypertension 43%, COPD 19%, and renal insufficiency 58%. In 47% of the patients, ischaemia was the origin of HF. In our registry, the prevalence of HF with preserved ejection fraction was 21%.ConclusionThe CHECK-HF registry will provide insight into the current, real world management of patient with chronic HF, including HF with reduced ejection fraction, preserved ejection fraction and mid-range ejection fraction, that will help define ways to improve quality of care. Drug and device therapy and guideline adherence as well as interactions with age, gender and co-morbidities will receive specific attention.
Our objective was to determine the diagnostic capabilities of combined prostate-specific membrane antigen (PSMA) PET/CT and sentinel node (SN) biopsy in PSMA PET/CT-negative patients for primary ...lymph node (LN) staging in prostate cancer (PCa) patients.
Between January 2017 and March 2019, retrospectively, all consecutive patients with diagnosed intermediate- or high-risk primary PCa who underwent preoperative PSMA PET/CT (
Ga or
F-DCFPyL) followed by robot-assisted radical prostatectomy and extended pelvic LN dissection (ePLND) were included. All patients without suspected LN metastases on PSMA PET/CT were considered candidates for SN biopsy with indocyanine green-
Tc-nanocolloid or
Tc-nanocolloid with free indocyanine green used as tracers. The ePLND was used as a reference standard.
Of 53 patients, 22 had positive PSMA PET/CT results and 31 underwent subsequent SN biopsy after negative PSMA PET/CT results. In total, 23 patients (43%) were pN1, of whom 6 (26%) had negative PSMA PET/CT results and underwent subsequent SN biopsy. The combined use of SN biopsy and PSMA PET/CT identified all pN1 patients (100% sensitivity; 95% confidence interval, 86%-100%) and performed correct nodal staging in 50 of 53 patients (94% diagnostic accuracy; 95% confidence interval, 84%-99%). SN biopsy identified significantly smaller LN metastases (median diameter, 2.0 mm; interquartile range, 1.0-3.8 mm) than PSMA PET/CT (median diameter, 5.5 mm; interquartile range, 2.6-9.3 mm;
= 0.007).
Combining both modalities led to a 94% accuracy for nodal staging in diagnosed intermediate- and high-risk primary PCa. Adding SN biopsy in patients with negative PSMA PET/CT results increased the combined sensitivity to 100% for detecting nodal metastases at ePLND. This diagnostic accuracy may provide valuable information for directing further treatment in PCa patients, such as the use of PSMA PET/CT and SN biopsy rather than ePLND as the preferred approach for staging before radiotherapy.
With the rise of fluorescence-guided surgery, it has become evident that different types of fluorescence signals can provide value in the surgical setting. Hereby a different range of targets have ...been pursued in a great variety of surgical indications. One of the future challenges lies in combining complementary fluorescent readouts during one and the same surgical procedure, so-called multi-wavelength fluorescence guidance. In this review we summarize the current clinical state-of-the-art in multi-wavelength fluorescence guidance, basic technical concepts, possible future extensions of existing clinical indications and impact that the technology can bring to clinical care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
Radioguided surgery has been widely used for clinical procedures such as sentinel node resections. In the (robot-assisted) laparoscopic setting radioguidance is realized using laparoscopic ...gamma probes, which have limited maneuverability. To increase the rotational freedom, a tethered DROP-IN gamma probe was designed. Here we present the first in vivo feasibility study of this technology in prostate cancer patients.
Methods
Ten patients scheduled for a sentinel node procedure received four injections into the prostate with (indocyanine green-)
99m
Technetium-nanocolloid and underwent preoperative imaging (lymphoscintigraphy and SPECT/CT). The DROP-IN probe was inserted via the assistant port, still permitting the insertion and usage of additional laparoscopic tools.
Results
The sentinel nodes were resected using the
da Vinci
® Si robot under guidance of DROP-IN gamma tracing and fluorescence imaging. The surgeon was able to independently maneuver the DROP-IN probe using the ProGrasp® forceps of the
da Vinci
® robot and distinguish sentinel nodes from background signal (such as the injection site).
Conclusions
Overall the DROP-IN design proves to be a valuable tool for robot-assisted radioguided surgery approaches.
EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor ...(HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% .The
P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.
The DROP-IN gamma probe was introduced to overcome the restricted manoeuvrability of traditional laparoscopic gamma probes. Through enhanced manoeuvrability and surgical autonomy, the DROP-IN ...promotes the implementation of radioguided surgery in the robotic setting.
To confirm the utility and safety profile of the DROP-IN gamma probe and to perform a comparison with the traditional laparoscopic gamma probe and fluorescence guidance.
Twenty-five prostate cancer patients were scheduled for a robot-assisted sentinel lymph node (SN) procedure, extended pelvic lymph node dissection, and prostatectomy at a single European centre.
After intraprostatic injection of indocyanine green (ICG)-99mTc-nanocolloid (n = 12) or 99mTc-nanocolloid + ICG (n = 13), SN locations were defined using preoperative imaging. Surgical excision of SNs was performed under image guidance using the DROP-IN gamma probe, the traditional laparoscopic gamma probe, and fluorescence imaging.
Intraoperative SN detection was assessed for the different modalities and related to anatomical locations. Patient follow-up was included (a median of 18 mo).
Overall, 47 SNs were pursued in vivo by the DROP-IN gamma probe, of which 100% were identified. No adverse events related to its use were observed. In vivo fluorescence imaging identified 91% of these SNs. The laparoscopic gamma probe identified only 76% of these SNs, where the detection inaccuracies appeared to be related to specific anatomical regions.
Owing to improved manoeuvrability, the DROP-IN probe yielded improved SN detection rates compared with the traditional gamma probe and fluorescence imaging. These findings underline that the DROP-IN technology provides a valuable tool for radioguided surgery in the robotic setting.
Radioguided robot-assisted surgery with the novel DROP-IN gamma probe is feasible and safe. It enables more efficient intraoperative identification of sentinel lymph nodes than can be achieved with a traditional laparoscopic gamma probe. The use of the DROP-IN probe in combination with fluorescence imaging allows for a complementary optical confirmation of node localisations.
The DROP-IN gamma probe integrates radioguided surgery within the robotic surgical setting. It appears that the DROP-IN gamma probe provides a higher detection rate of sentinel nodes in prostate cancer than the traditional laparoscopic gamma probe or fluorescence imaging.
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