Highlights • MSC-educated macrophages (MEMs) are an alternatively activated macrophage subset • MEMs secrete high levels of IL-6 controlled in part by JAK/STAT, arginase and COX • Infusion of MEMs ...lead to better survival than MSCs in established xenogeneic GVHD • MEMs improve survival from radiation injury in part through host fibroblasts
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia
. This result suggests that leukaemia uses unique ...mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
Recent studies have shown that growth hormone (GH) can reduce neuronal loss after hypoxic-ischemic injury (HI) in neonatal and juvenile rat brains. Here, we investigated whether GH exerts its ...neuroprotective role through an anti-apoptotic effect in neonatal rat brains damaged by severe HI. Gross and histological observations showed that the extent of brain damage was found to be reduced in GH-treated brain at E7 after injury. In a terminal transferase-mediated dUTP nick-end-labeling (TUNEL) study, TUNEL-positive apoptotic cells were localized only at the damaged region in animals treated with saline, which was confirmed by an electron microscopy. In an immunohistochemical study with anti-bcl-2, -bax, -bad, -neuronal nitric oxide synthase (nNOS), -inducible NOS (iNOS) and -endothelial NOS (eNOS) antibodies, we observed that bax, bad, iNOS and eNOS were elevated in the saline-treated group. This study thus suggests that the protective role of GH against HI injury is mediated thorough an anti-apoptotic effect, which offers the possibility of a GH application for the treatment of neonatal HI encephalopathy.
Colloidal assemblies of nanoparticles possess both the intrinsic and collective properties of their constituent nanoparticles, which are useful in applications where ordinary nanoparticles are not ...well suited. Here, we report an immunoassay technique based on colloidal nanoparticle assemblies made of iron oxide nanoparticles (magnetic substrate) and manganese-doped zinc sulfide (ZnS:Mn) nanoparticles (photoluminescent substrate), both of which are functionalized with antibodies to capture target proteins in a sandwich assay format. After magnetic isolation of the iron oxide nanoparticle assemblies and their bound ZnS:Mn nanoparticle assemblies (MZSNAs), photoluminescence of the remaining MZSNAs is measured for the protein quantification, eliminating the need for washing steps and signal amplification. Using human C-reactive protein as a model biomarker, we achieve a detection limit of as low as 0.7 pg/mL, which is more than 1 order of magnitude lower than that of enzyme-linked immunosorbent assay (9.1 pg/mL) performed using the same pair of antibodies, while using only one-tenth of the antibodies. We also confirm the potential for multiplex detection by using two different types of photoluminescent colloidal nanoparticle assemblies simultaneously.
Previous studies have successfully shown evidence for parasitic infections in human remains from various archaeological sites. However, in the case of Korea, since there have been very few ...paleoparasitological reports published, pre-20th century parasitic infection patterns remain obscure. Therefore, in order to partly fill this gap, we are reporting on a case of paleoparasitic infection from the feces of a 15th century child mummy from Yangju, Korea. In the course of the present study, we found the eggs of Clonorchis sinensis, Ascaris lumbricoides, and Trichuris trichiura in the feces of the mummy. Trichuris trichiura eggs were found in far greater numbers than other parasite eggs; in fact, intact bipolar plugs were clearly observed and even the larvae were still visible in some eggs. The eggs of C. sinensis and A. lumbricoides were also well preserved, though not in as great a number. Since we could find a number of well-preserved larvae-containing eggs, we are encouraged that successful extraction, amplification, and sequence determination of ancient DNA from the paleoparasite eggs might be possible in future studies. With additional paleoparasitological investigation using feces from Korean mummies, we hope that a history of parasite infection in Korea will be reconstructed.
Mesenchymal stromal/stem cells (MSCs) are considered promising cellular therapeutics in the fields of tissue engineering and regenerative medicine. MSCs secrete high concentrations of ...immunomodulatory cytokines and growth factors, which exert paracrine effects on infiltrating immune and resident cells in the wound microenvironment that could favorably promote healing after acute injury. However, better spatial delivery and improved retention at the site of injury are two factors that could improve the clinical application of MSCs. In this study, we utilized thiol-ene Michael-type addition for rapid encapsulation of MSCs within a gelatin/poly(ethylene glycol) biomatrix. This biomatrix was also applied as a provisional dressing to full thickness wounds in Sprague–Dawley rats. The three-way interaction of MSCs, gelatin/poly(ethylene glycol) biomatrices, and host immune cells and adjacent resident cells in the wound microenvironment favorably modulated wound progression and host response. In this model we observed attenuated immune cell infiltration, lack of foreign giant cell (FBGC) formation, accelerated wound closure and re-epithelialization, as well as enhanced neovascularization and granulation tissue formation by 7days. The MSC entrapped in the gelatin/poly(ethylene glycol) biomatrix localized cell presentation adjacent to the wound microenvironment and thus mediated the early resolution of inflammatory events and facilitated the proliferative phases in wound healing.
Background
Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology ...guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke.
Study Design
This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10‐year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA).
Results
Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83‐99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them.
Conclusion
The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.
This study aims to assess the clinical utility of CK-MB measurement in patients suspected of acute coronary syndrome (ACS).
All CK-MB and troponin T measurements performed <1h apart during the study ...period were obtained and analyzed for concordance. A total of 1214 cases with discordant biomarkers results were found. Retrospective review of electronic health records (EHRs) was performed to assess the clinical impact, if any, of the discordant biomarkers results.
In 401 cases, CK-MB concentrations were increased whereas troponin T concentrations were negative at <0.01ng/ml. In this group, clinical interpretations included, rhabdomyolysis, demand ischemia, and drug intoxication. No additional investigations for ACS were conducted in this group. Among the remaining 813 cases, troponin T concentrations were increased in the presence of a normal CK-MB result. In this group, the discordant normal CK-MB lowered suspicion for ACS in only 22 cases (2.7%). Most common interpretations for isolated positive troponin were demand ischemia and impaired renal function. In most cases, discordant CK-MB results were not considered a significant finding.
In the setting of suspected ACS, CK-MB has limited clinical impact when contemporary troponin assay results are available.
•Clinical utility of CK-MB measurement was assessed following retrospective medical records review•CK-MB results exhibit considerable degree of discrepancy with Troponin results•Most of the CK-MB result discrepancies are not interpreted or considered by clinicians•None of the isolated elevation of CK-MB results were used to indicate acute coronary syndrome•Clinical utility of CK-MB measurement appears limited when screening for acute coronary syndrome
Immune checkpoint blockade therapy has been successful in treating some types of cancers but has not shown clinical benefits for treating leukemia. This result suggests that leukemia exploits unique ...escape mechanisms. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukemia cells. It remains unknown whether these receptors can initiate immune-related primary signaling in tumor cells. Here we show that LILRB4, an ITIM-containing receptor and a monocytic leukemia marker, supports tumor cell infiltration into tissues and suppresses T cell activity via ApoE/LILRB4/SHP-2/uPAR/Arginase-1 signaling axis in acute myeloid leukemia (AML) cells. Blocking LILRB4 signaling using knockout and antagonistic antibody approaches eliminated AML development. Thus, LILRB4 orchestrates tumor invasive pathways in monocytic leukemia cells by creating an immune-suppressive microenvironment. LILRB4 represents an attractive target for treatment of monocytic AML.
Deng:Immune-Onc Therapeutics Inc.: Patents & Royalties. Gui:Immune-Onc Therapeutics Inc.: Patents & Royalties. Kim:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zheng:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zhang:Immune-Onc Therapeutics Inc.: Patents & Royalties. An:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zhang:Immune-Onc Therapeutics Inc.: Patents & Royalties.
An 8.0 GHz to 12.2 GHz PLL with a capacitor multiplier-based active loop filter is designed in a 28 nm digital CMOS process. A passive loop filter-based version of the PLL is also implemented for ...comparison. While the PLL area is comparable to that of digital PLLs, the PLL performance is as good as that of an analog PLL that employs a passive loop filter. The capacitor multiplier-based active loop filter PLL has a jitter performance of 198 fs (rms), while its passive loop filter-based counterpart shows a jitter performance of 195 fs (rms). The PLL occupies 0.093 mm 2 and consumes 15.5 mA at 1.0V.
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