The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach their site of action, the cytosol of target cells. Lipid nanoparticles, including liposomes, are ...commonly employed as siRNA carrier systems to overcome this hurdle, although their widespread use remains limited due to a lack of delivery efficiency. More recently, nature's own carriers of RNA, extracellular vesicles (EVs), are increasingly being considered as alternative siRNA delivery vehicles due to their intrinsic properties. However, they are difficult to load with exogenous cargo. Here, EV–liposome hybrid nanoparticles (hybrids) are prepared and evaluated as an alternative delivery system combining properties of both liposomes and EVs. It is shown that hybrids are spherical particles encapsulating siRNA, contain EV‐surface makers, and functionally deliver siRNA to different cell types. The functional behavior of hybrids, in terms of cellular uptake, toxicity, and gene‐silencing efficacy, is altered as compared to liposomes and varies among recipient cell types. Moreover, hybrids produced with cardiac progenitor cell (CPC) derived‐EVs retain functional properties attributed to CPC‐EVs such as activation of endothelial signaling and migration. To conclude, hybrids combine benefits of both synthetic and biological drug delivery systems and might serve as future therapeutic carriers of siRNA.
The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach the site of action. In this work, extracellular vesicle (EV)–liposome hybrid nanoparticles are evaluated as siRNA drug delivery vehicle, and it is shown that these hybrid nanoparticles functionally deliver siRNA and at the same time retain important biological functions attributed to EVs.
This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).
...Patients were randomized 1:1:1 to veliparib 240 mg twice daily (BID) for 14 days plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.
Overall (
= 181), PFS was improved with veliparib throughout versus control hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88;
= 0.059; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.
Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.
Chromium nanoparticles are formed using superfluid helium droplets as the nanoreactors, which are strongly ferromagnetic. The transition from antiferromagentism to ferromagnetism is attributed to ...atomic‐scale disorder in chromium nanoparticles, leading to abundant unbalanced surface spins. Theoretical modeling confirms a frustrated aggregation process in superfluid helium due to the antiferromagnetic nature of chromium.
Highbush blueberry production has expanded worldwide in recent decades. To safeguard future yields, it is essential to understand if insect pollination is limiting current blueberry production and ...which insects contribute to pollination in different production regions.
We present a systematic review including a set of meta‐analyses on insect‐mediated pollination in highbush blueberry. We summarize the geographic distribution of research, the abundance of different pollinator taxa and their relative pollination contributions. Using raw data from 21 studies, totalling 496 site replicates, we determine the degree of pollination service and pollen limitation (i.e. combining open pollination levels with experimental bagged and/or hand pollination treatments), as well as the contribution of honeybees and wild bees to pollination (i.e. observational, open pollination).
Most studies originate from North America, focusing on only a few cultivars. Honeybees are the dominant pollinator, and wild bees are occasionally abundant. Wild bees are more efficient pollinators on a single‐visit basis compared to honeybees, which increases their relative pollination contribution compared to their relative abundance.
Insect‐mediated pollination services increased blueberry fruit set, berry weight and seed set (R2 values: 64.8%, 75.9% and 75.2% respectively). We often detected pollen limitation, indicated by an increase in fruit set, berry weight and seed set (R2: 10.1%, 18.2% and 21.5%, respectively), with additional hand pollination. Increasing visitation of honeybees and wild bees contributed to blueberry pollination by increasing fruit set (R2: 5.4% and 3.5%), berry weight (R2: 6.5% and 2.8%) and seed set (R2: 6.4% and 3.8%) respectively. Bee contributions to fruit set and berry weight were variable across regions.
Synthesis and application: A diverse community of insects, primarily bees, contributes to highbush blueberry pollination and yield. However, pollination deficits are common. The finding that both honeybees and wild bees enhance pollination highlights the possibility of adopting different management strategies that utilize honeybees, wild bees or both depending on the specific context and region. This further emphasizes the general importance of conserving pollinator health and diversity. Our synthesis highlights data gaps and areas for future research to better understand the pollination contribution of different pollinators to crops that are expanding globally.
A diverse community of insects, primarily bees, contributes to highbush blueberry pollination and yield. However, pollination deficits are common. The finding that both honeybees and wild bees enhance pollination highlights the possibility of adopting different management strategies that utilize honeybees, wild bees or both depending on the specific context and region. This further emphasizes the general importance of conserving pollinator health and diversity. Our synthesis highlights data gaps and areas for future research to better understand the pollination contribution of different pollinators to crops that are expanding globally.
Objectives
To develop a transmural pathway for healthcare professionals across institutions to monitor the recovery of hip fracture patients. The secondary objectives were to evaluate the pathway's ...feasibility and initial outcomes.
Design
Prospective cohort study.
Method
Stakeholders of the hospital and geriatric rehabilitation institutions implemented a transmural monitoring pathway in which different geriatric health domains were monitored during three phases: The in-hospital, inpatient rehabilitation, and outpatient follow-up phase. The outcomes for the first 291 patients and the feasibility of the pathway were evaluated. If the outcomes of the clinimetrics significantly improved over time, progress in functional recovery was assumed. Feasibility was assessed according to the rate of adherence to the clinimetric tests.
Results
During the in-hospital phase, patients showed a decline in functional level (the Katz index of independence in Activities of Daily Living (Katz-ADL) pre-fracture vs. discharge: 0 (0–2) vs. 4 (4–5), P < 0.001). Patients, in which 78.6% (n = 140) had cognitive impairment and 41.2% had malnutrition, showed the most progress (Katz-ADL 2 (1–3)) during the inpatient rehabilitation phase. In the outpatient follow-up phase, recovery remained ongoing, but most patients had not returned to their pre-fracture functional levels (Katz-ADL 1 (1–3)). The pathway feasibility during the first phase was excellent (>85%), whereas room for improvement existed during other phases (<85%).
Conclusion
The transmural monitoring pathway provides insight into the entire recovery process for all involved healthcare professionals. Patients showed the most progress during the rehabilitation phase. The pathway feasibility was excellent during the in-hospital phase, but improvements could be made during other phases.
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural ...alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug–drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Real-time assessment of excised tissue may help to improve surgical results in breast tumor surgeries. Here, as a step towards this purpose, the potential of second and third harmonic generation ...(SHG, THG) microscopy is explored. SHG and THG are nonlinear optical microscopic techniques that do not require labeling of tissue to generate 3D images with intrinsic depth-sectioning at sub-cellular resolution. Until now, this technique had been applied on fixated breast tissue or to visualize the stroma only, whereas most tumors start in the lobules and ducts. Here, SHG/THG images of freshly excised unprocessed healthy human tissue are shown to reveal key breast components-lobules, ducts, fat tissue, connective tissue and blood vessels, in good agreement with hematoxylin and eosin histology. DNA staining of fresh unprocessed mouse breast tissue was performed to aid in the identification of cell nuclei in label-free THG images. Furthermore, 2- and 3-photon excited auto-fluorescence images of mouse and human tissue are collected for comparison. The SHG/THG imaging modalities generate high quality images of freshly excised tissue in less than a minute with an information content comparable to that of the gold standard, histopathology. Therefore, SHG/THG microscopy is a promising tool for real-time assessment of excised tissue during surgery.
Millions of women worldwide have silicone breast implants. It has been reported that implant failure occurs in approximately a tenth of patients within 10 years, and the consequences of dissemination ...of silicone debris are poorly understood. Currently, silicone detection in histopathological slides is based on morphological features as no specific immunohistochemical technique is available. Here, we show the feasibility and sensitivity of stimulated Raman scattering (SRS) imaging to specifically detect silicone material in stained histopathological slides, without additional sample treatment. Histology slides of four periprosthetic capsules from different implant types were obtained after explantation, as well as an enlarged axillary lymph node from a patient with a ruptured implant. SRS images coregistered with bright‐field images revealed the distribution and quantity of silicone material in the tissue. Fast and high‐resolution imaging of histology slides with molecular specificity using SRS provides an opportunity to investigate the role of silicone debris in the pathophysiology of implant‐linked diseases.
Leaking silicone material from breast implants has been hypothesized to be involved in implant‐related ailments. In tissue slides for conventional pathology, silicone material cannot be detected with certainty. We demonstrate an advanced label‐free imaging technique that proves the presence of silicone. The resulting image can be overlaid (in green) on a conventional histology slide, as shown here for breast implant capsule tissue. Scale bar: 100 μm.
Inflammation is an important component of various cancers and its inflammatory cells and mediators have been shown to have prognostic potential. Tumor-infiltrating mast cells can promote tumor growth ...and angiogenesis, but the mechanism of mast cell activation is unclear. In earlier studies, we demonstrated that immunoglobulin free light chains (FLC) can trigger mast cells in an antigen-specific manner. Increased expression of FLC was observed within stroma of various human cancers including those of breast, colon, lung, pancreas, kidney and skin, and FLC expression co-localized with areas of mast cell infiltration. In a large cohort of breast cancer patients, FLC expression was shown associated with basal-like cancers with an aggressive phenotype. Moreover, lambda FLC was found expressed in areas of inflammatory infiltration and its expression was significantly associated with poor clinical outcome. Functional importance of FLCs was shown in a murine B16F10 melanoma model, where inhibition of FLC-mediated mast cell activation strongly reduced tumor growth. Collectively, this study identifies FLCs as a ligand in the pro-tumorigenic activation of mast cells. Blocking this pathway may open new avenues for the inhibition of tumor growth, while immunohistochemical staining of FLC may be helpful in the diagnosis and prognosis of cancer.
PDF
