Background
Although the pathology and bacterial status of the “normal” bone stump after operation of diabetic foot osteomyelitis (DFO) are of great significance for the prognosis of foot wounds, ...there are only a few studies on this topic; hence, it is clinically relevant and urgent to study this topic.
Methods
The data of 57 inpatients with DFO from June 2021 to April 2022 were collected, all of whom had DFO in the forefoot and underwent conservative surgery. After the surgical removal of necrotic bone, bone biopsies were taken from the necrotic phalangeal bone and the reserved “normal” metatarsal stump. They were cultured, after which antibiotic susceptibility test and pathological screening were carried out. According to clinical judgment, inpatients’ wounds were divided into metatarsal affected group and metatarsal unaffected group. We then compared and analyzed the pathological and bacterial characteristics of preserved “normal” bone stump and its effect on wound healing and prognosis.
Results
The poor concordance rate between deep soft tissue culture and infected phalange culture was only 19.3%. The deep soft tissue (72.6%), infected phalange (70.7%), and metatarsal stump (71.4%) were mainly infected with gram-negative Bacillus. The proportion of
Enterococcus spp.
increased significantly in bone tissue.
Acinetobacter baumannii
had the highest drug resistance (88%, 22/25). There was no significant difference in several clinical characteristics and wound healing regardless of whether their metatarsal stumps were affected. Most reserved “normal” metatarsal stumps (84.2%, 48/57) were positive by pathological diagnosis and bacterial culture testing; only 15.7% (9/57) samples were truly sterile. Only 8.3% (4/48) of the former patients healed within 6 months; whereas, all the latter (9/9) patients healed within 6 months. However, the majority (89.6%, 43/48) could heal. There was no difference in operations, skin grafting, negative pressure wound therapy, and mortality between the two groups.
Conclusion
The most reserved “normal” metatarsal stumps have been invaded by bacteria. However, the majority stumps can be preserved, and the wound will eventually be healed according to the pathological and bacterial culture results.
Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to autocrine and paracrine growth stimulation in several human malignant tumors, including breast cancer. However, the ...mechanisms underlying the carcinogenic actions of FGF18 remain unclear.
The transcription level of FGF18 under the hypoxic condition was detected with quantitative PCR (qPCR). A wound-healing assay was performed to assess the role of FGF18 in cell migration. A clonogenicity assay was used to determine whether FGF18 silencing affected cell clonogenicity. Western blotting was performed to investigate Akt/GSK3β/β-catenin pathway protein expression. Binding of β-catenin to the target gene promoter was determined by chromatin immunoprecipitation (ChIP) assays.
FGF18 promoted the epithelial-mesenchymal transition (EMT) and migration in breast cancer cells through activation of the Akt/GSK3β/β-catenin pathway. FGF18 increased Akt-Ser473 and -Thr308 phosphorylation, as well as that of GSK3β-Ser9. FGF18 also enhanced the transcription of proliferation-related genes (CDK2, CCND2, Ki67), metastasis-related genes (TGF-β, MMP-2, MMP-9), and EMT markers (Snail-1, Snail-2, N-cadherin, vimentin, TIMP1). β-catenin bound to the target gene promoter on the ChIP assay.
FGF18 contributes to the migration and EMT of breast cancer cells following activation of the Akt/GSK3β/β-catenin pathway. FGF18 expression may be a potential prognostic therapeutic marker for breast cancer.
Abstract
Clinical immunity against
Plasmodium falciparum
infection develops in residents of malaria endemic regions, manifesting in reduced clinical symptoms during infection and in protection ...against severe disease but the mechanisms are not fully understood. Here, we compare the cellular and humoral immune response of clinically immune (0-1 episode over 18 months) and susceptible (at least 3 episodes) during a mild episode of
Pf
malaria infection in a malaria endemic region of Malawi, by analysing peripheral blood samples using high dimensional mass cytometry (CyTOF), spectral flow cytometry and single-cell transcriptomic analyses. In the clinically immune, we find increased proportions of circulating follicular helper T cells and classical monocytes, while the humoral immune response shows characteristic age-related differences in the protected. Presence of memory CD4
+
T cell clones with a strong cytolytic ZEB2
+
T helper 1 effector signature, sharing identical T cell receptor clonotypes and recognizing the
Pf
-derived circumsporozoite protein (CSP) antigen are found in the blood of the
Pf
-infected participants gaining protection. Moreover, in clinically protected participants, ZEB2
+
memory CD4
+
T cells express lower level of inhibitory and chemotactic receptors. We thus propose that clonally expanded ZEB2
+
CSP-specific cytolytic memory CD4
+
Th1 cells may contribute to clinical immunity against the sporozoite and liver-stage
Pf
malaria.
Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating ...insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.
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•Two meals per period entrains insulin and leptin oscillations•Insulin and leptin oscillations drive the cellular, immune, and metabolic remodeling of sWAT•sWAT remodeling leads to metabolic flexibility and inflammation resolution in eWAT•Recreating insulin and leptin oscillations pharmacologically recapitulates sWAT remodeling
Mattar et al. show that two meals per period entrains insulin and leptin oscillations to drive subcutaneous fat browning and metabolic flexibility. Targeting insulin or leptin signaling or ILC2 cell recruitment or tissue denervation each blocks subcutaneous fat browning in food-entrained mice, while reconstituting endocrine oscillations facilitates adipose browning.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
FMR1, a new m
6
A reader, is known to be involved in the regulation of cancer progression. However, its role, regulatory mechanism, and clinical significance in colorectal cancer (CRC) are ...elusive. Here, we showed that FMR1 was upregulated in CRC, and it promoted proliferation and metastasis of CRC cells in vitro and in vivo. Mechanically, FMR1 recognized the m
6
A-modification site in EGFR mRNA, a key molecule in cancer occurrence and targeted therapy, sustained its stability and maintained its expression in an m
6
A-dependent manner, thereby promoting the tumorigenesis and metastasis of CRC. And the effect of FMR1 knockdown in CRC cells could be abolished by METTL3. Furthermore, FMR1 shRNA plasmid carried by attenuated
Salmonella
has an effective anti-tumor effect in vivo. Collectively, we identified the METTL3/FMR1/EGFR axis in the progression of CRC. This novel mechanism indicated that the METTL3/FMR1/EGFR axis is a potential target for early therapeutic intervention in CRC progression.
The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective ...sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1
mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
Abstract Esophageal cancer is among the most deadly malignant diseases. However, the genetic factors contributing to its occurrence are poorly understood. Multiple studies with large clinic-based ...cohorts revealed that variations of the phospholipase C epsilon (PLCE1) gene were associated with esophageal cancer susceptibility. However, the causative role of PLCE1 in esophageal cancer is not clear. We inactivated the functional alleles of PLCE1 by CRISPR/Cas9 genome editing technology. The resultant PLCE1 inactivated cells were analyzed both in vitro and in vivo . Our results showed that loss of PLCE1 dramatically decreased the invasion and proliferation capacity of esophageal carcinoma cells in vitro . Moreover, such PLCE1 inactivated tumor grafts exhibited significantly decreased tumor size in mice. We found that PLCE1 was required to maintain protein level of snail a key transcription factor responsible for invasion. Our further transcriptomic data revealed that deficient cells were significantly decreased in expression of genes enriched as targets of Snail. Strikingly, recovery of Snail protein at least partially rescued the invasion and proliferation capacity in PLCE1 inactivated cells. In ESCC clinical specimens, PLCE1 was correlated with tumor stage ( P < .0001). Interestingly, PLCE1 expression was positively correlated Snail by immunohistochemistry in such specimens ( P < .0001). Therefore, our functional experiments showed the essential roles of PLCE1 in esophageal carcinoma cells and provided evidences that targeting PLCE1 and its downstream molecules could be effective therapies for esophageal cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the Hadamard transform (HT) near-infrared (NIR) spectrometer, there are defects that can create a nonuniform distribution of spectral energy, significantly influencing the absorbance of the whole ...spectrum, generating stray light, and making the signal-to-noise ratio (SNR) of the spectrum inconsistent. To address this issue and improve the performance of the digital micromirror device (DMD) Hadamard transform near-infrared spectrometer, a split waveband scan mode is proposed to mitigate the impact of the stray light, and a new Hadamard mask of variable-width stripes is put forward to improve the SNR of the spectrometer. The results of the simulations and experiments indicate that by the new scan mode and Hadamard mask, the influence of stray light is restrained and reduced. In addition, the SNR of the spectrometer also is increased.
Efficiency of reprogramming of human cells into induced pluripotent stem cells (iPSCs) has remained low. We report that individual adult human CD49f+ long-term hematopoietic stem cells (LT-HSCs) can ...be reprogrammed into iPSCs at close to 50% efficiency using Sendai virus transduction. This exquisite sensitivity to reprogramming is specific to LT-HSCs, since it progressively decreases in committed progenitors. LT-HSC reprogramming can follow multiple paths and is most efficient when transduction is performed after the cells have exited G0. Sequencing of 75 paired skin fibroblasts/LT-HSC samples collected from nine individuals revealed that LT-HSCs contain a lower load of somatic single-nucleotide variants (SNVs) and indels than skin fibroblasts and accumulate about 12 SNVs/year. Mutation analysis revealed that LT-HSCs and fibroblasts have very different somatic mutation signatures and that somatic mutations in iPSCs generally exist prior to reprogramming. LT-HSCs may become the preferred cell source for the production of clinical-grade iPSCs.
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•Single adult human LT-HSCs can be reprogrammed into iPSCs at close to 50% efficiency.•LT-HSCs contain less somatic variants than skin fibroblasts.•LT-HSCs may become the preferred source for the production of clinical-grade iPSCs.
Wang et al. show that single adult human long-term hematopoietic stem cells can be reprogrammed into induced pluripotent stem cells at close to 50% efficiency and contain fewer somatic single-nucleotide variants and indels than skin fibroblasts. They may become the preferred source for the production of clinical-grade iPSCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To produce blood platelets, megakaryocytes elaborate proplatelets, accompanied by expansion of membrane surface area and dramatic cytoskeletal rearrangements. The invaginated demarcation membrane ...system (DMS), a hallmark of mature cells, has been proposed as the source of proplatelet membranes. By direct visualization of labeled DMS, we demonstrate that this is indeed the case. Late in megakaryocyte ontogeny, the DMS gets loaded with PI-4,5-P2, a phospholipid that is confined to plasma membranes in other cells. Appearance of PI-4,5-P2 in the DMS occurs in proximity to PI-5-P-4-kinase α (PIP4Kα), and short hairpin (sh) RNA-mediated loss of PIP4Kα impairs both DMS development and expansion of megakaryocyte size. Thus, PI-4,5-P2 is a marker and possibly essential component of internal membranes. PI-4,5-P2 is known to promote actin polymerization by activating Rho-like GTPases and Wiskott-Aldrich syndrome (WASp) family proteins. Indeed, PI-4,5-P2 in the megakaryocyte DMS associates with filamentous actin. Expression of a dominant-negative N-WASp fragment or pharmacologic inhibition of actin polymerization causes similar arrests in proplatelet formation, acting at a step beyond expansion of the DMS and cell mass. These observations collectively suggest a signaling pathway wherein PI-4,5-P2 might facilitate DMS development and local assembly of actin fibers in preparation for platelet biogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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