An afucosylated anti-CD32b monoclonal antibody induced platelet-mediated adverse events in a human Fcγ receptor transgenic mouse model and its potential human translatability

Toxicological sciences : an official journal of the Society of Toxicology

2021 Oct 23

Wolf, B;Jeliazkova-Mecheva, V;Del Rio-Espinola, A;Boisclair, J;Walker, D;Cochin De Billy, B;Flaherty, M;Flandre, T;
PMID: 34687301 | DOI: 10.1093/toxsci/kfab124

To assess the safety and tolerability of NVS32b, a monoclonal, afucosylated, anti-CD32b (FCGR2B) antibody we used a humanized transgenic (Tg) mouse model that expresses all human Fc gamma receptors (FCGRs) while lacking all mouse FCGRs. Prior to its use, we extensively characterized the model. We found expression of all human FCGRs in a pattern similar to humans with some exceptions, such as low CD32 expression on T cells (detected with the pan CD32 antibody but more notably with the CD32b-specific antibody), variation in the transgene copy number, integration of additional human genes, and overall higher expression of all FCGRs on myeloid cells compared to human. Unexpectedly, NVS32b induced severe acute generalized thrombosis in huFCGR mice upon iv dosing. Mechanistic evaluation on huFCGR and human platelets revealed distinct binding, activation and aggregation driven by NVS32b in both species. In huFCGR mice, the anti-CD32b antibody NVS32b binds platelet CD32a via both Fc and/or CDR (complementarity determining region) causing their activation while in human, NVS32b-binding requires platelet pre-activation and interaction of platelet CD32a via the Fc portion and an unknown platelet epitope via the CDR portion of NVS32b. We deemed the huFCGR mice to be over-predictive of the NVS32b-associated human thrombotic risk. Impact: In this study we elucidated the mechanism based on the thrombotic adverse events observed in huFCGR mice upon NVS32B dosing and were able to identify this safety liability which led to program termination. Therefore, this mouse model could be useful in research of immunotherapies targeting or involving FCGRs. Potential biological implications resulting from species differences in the FCGR expression pattern are nevertheless important to consider.

Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model

Cell and tissue research

2021 Jul 21

Namba, T;Ichii, O;Nakamura, T;Masum, MA;Otani, Y;Hosotani, M;Elewa, YHA;Kon, Y;
PMID: 34287716 | DOI: 10.1007/s00441-021-03495-8

The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36α, IL-36β, IL-36γ) and antagonists (IL-36Ra, IL-38). We previously reported IL-36α overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ-Faslpr/lpr mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Faslpr/lpr mice exhibited disease onset from 3 months and severe nephritis at 6-7 months (early and late stages, respectively). Briefly, IL-36γ and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36α, IL-36β, IL-36Ra, and IL-38 was induced in MRL/MpJ-Faslpr/lpr mice. IL-36α expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44+-activated parietal epithelial cells (PECs) also exhibited higher IL-36α-positive rates, particularly in males. IL-36β and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36α and IL-38 positively correlated with nephritis severity. Similar to IL-36α, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ-Faslpr/lpr and healthy MRL/MpJ mice possessed IL-36Ra+ smooth muscle cells in kidney arterial tunica media at both stages. IL-36γ was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ-Faslpr/lpr mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-κB- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36α-dominant imbalance could strongly impact nephritis deterioration.

APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer\'s disease and age-matched non-demented brains

Molecular brain

2021 Jul 08

Ojo, JO;Reed, JM;Crynen, G;Vallabhaneni, P;Evans, J;Shackleton, B;Eisenbaum, M;Ringland, C;Edsell, A;Mullan, M;Crawford, F;Bachmeier, C;
PMID: 34238312 | DOI: 10.1186/s13041-021-00803-9

Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE variants (APOE2 and APOE3) has been largely unexplored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains with different APOE genotypes. We first interrogated changes between healthy control cases to identify underlying genotype specific effects in cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. Oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction were the top significant pathways in E2E2 vs E3/E3cases. We also identified AD-dependent changes and their interactions with APOE genotype and found the highest number of significant proteins from this interaction was observed in the E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell-type specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E3/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E4/E4 cases. These proteomic changes provide novel insights into the longstanding link between APOE4 and cerebrovascular dysfunction, implicating a role for impaired autophagy, ER stress, and mitochondrial bioenergetics. These APOE4 dependent changes we identified could provide novel cerebrovascular targets for developing disease modifying strategies to mitigate the effects of APOE4 genotype on AD pathogenesis.

Peripheral Contribution of BDNF/TrkB signaling in Mediating Oral Cancer Pain

The Journal of Pain

2021 May 01

Arris, D;Grayson, M;Wu, P;Ganatra, S;Valenzuela, V;Ruparl, S;
| DOI: 10.1016/j.jpain.2021.03.012

Background: Oral cancer pain is debilitating and understanding mechanisms for it is critical to develop treatment strategies. Brain-derived neurotrophic factor (BDNF) signaling is elevated in oral tumor biopsies and has been reported to promote tumor progression. However, whether BDNF signaling in oral tumors contributes to cancer-induced pain is not known. Therefore, the current study evaluates a novel peripheral role of BDNF/TrkB signaling in oral cancer pain. Using an orthotopic mouse tongue cancer pain model, we determine BDNF levels and expression tumor-tongue and normal tongue tissues using ELISA and immunohistochemistry. Additionally, we evaluated the effect of local administration of BDNF neutralizing Ab as well as TrkB receptor antagonist (ANA12) in reversing pain-like behaviors in vivo. Further, we identified the sensory fiber type affected by local ANA12 treatment in tumor-bearing tongues using single-fiber tongue-nerve electrophysiology and characterized TrkB isoform expression in sensory neuronal subtypes innervating mouse tongue. Our data demonstrated that BDNF levels were up-regulated in superfusates and lysates of tumor tongues over normal tongues and that BDNF was expressed by the cancer cells within the tumor. Neutralization of BDNF or inhibition of TrkB activity (ANA12) within the tumor-bearing tongue reversed tongue-tumor induced pain-like behaviors. Single-fiber recordings of tongue-nerve preparations revealed that ANA12 reversed tumor-induced mechanical sensitivity of A-slow high threshold mechanoreceptors. Single-cell RTPCR of lingual neurons demonstrated expression of full-form TrkB and truncated TrkB in distinct neuronal subtypes. Our data suggests that BDNF is released from oral cancer cells at the site of tumor growth and activates TrkB-expressing lingual sensory fibers, thereby contributing to oral cancer pain. This is a novel finding and the first demonstration of a peripheral role for BDNF signaling in oral cancer pain. Targeting BDNF signaling peripherally may prove to be an effective treatment for cancer-induced pain as well as tumorigenesis.

High-fat diet induces follicular hyperkeratinization and predisposes to develop neutrophilic folliculitis in mice

The Journal of allergy and clinical immunology

2021 Mar 10

Nakamizo, S;Honda, T;Sato, T;Mamun, MA;Chow, Z;Duan, K;Lum, J;Tan, KJ;Tomari, K;Sato, R;Kitoh, A;Tay, ASL;Common, JEA;Guan, NL;Setou, M;Ginhoux, F;Kabashima, K;
PMID: 33713763 | DOI: 10.1016/j.jaci.2021.02.032

Neutrophilic folliculitis is an inflammatory condition of hair follicles. In some neutrophilic folliculitis, such as acne and hidradenitis suppurativa, follicular hyperkeratosis is also observed. Neutrophilic folliculitis is often induced and/or exacerbated by high-fat diet (HFD). However, the molecular mechanisms by which HFD affects neutrophilic folliculitis are not fully understood. To elucidate how HFD promotes the development of neutrophilic folliculitis. Mice were fed with HFD, and the skin was subjected to histological, RNA-sequencing and imaging mass spectrometry analyses. Phorbol 12-myristate 13-acetate (PMA) was used as an irritant to the skin to examine the effect of HFD on neutrophil accumulation around the hair follicles. Histological analysis revealed follicular hyperkeratosis in the skin of HFD-fed mice. RNA-sequencing analysis showed that genes related to keratinization, especially in upper hair follicular keratinocytes, were significantly upregulated in HFD-fed mice. Application of PMA to the skin induced neutrophilic folliculitis in HFD-fed mice, but not in normal diet (ND)-fed mice. Accumulation of neutrophils in the skin and around hair follicles was dependent on CXCR2 signaling, and CXCL1, a CXCR2 ligand, was produced mainly by hair follicular keratinocytes. Imaging mass spectrometry analysis revealed an increase of fatty acids in the skin, including oleic acids and palmitoleic acids in HFD-fed mice. Application of these fatty acids to the skin induced follicular hyperkeratosis, and caused PMA-induced neutrophilic folliculitis even in ND-fed mice. HFD can facilitate the development of neutrophilic folliculitis with the induction of hyperkeratosis of hair follicles and increased neutrophil infiltration around the hair follicles via CXCR2 signaling.

Cytopathology of Bronchoalveolar Lavages in COVID-19 Pneumonia: A Pilot Study

Cancer cytopathology

2021 Mar 10

Canini, V;Bono, F;Calzavacca, P;Capitoli, G;Foti, G;Fraggetta, F;Galimberti, S;Gianatti, A;Giani, M;Nasr, A;Paciocco, G;Pagni, F;Rona, R;L'Imperio, V;
PMID: 33690991 | DOI: 10.1002/cncy.22422

Bronchoalveolar lavage (BAL) in patients with severe coronavirus disease 2019 (COVID-19) may provide additional and complementary findings for the management of these patients admitted to intensive care units (ICUs). This study addresses the cytological features of the infection and highlights the more influential inflammatory components. The correlation between pathological variables and clinical data is also analyzed. The authors performed a retrospective analysis of the cytopathological features of BAL in 20 COVID-19 patients and 20 members of a matched cohort from a critical ICU who had acute respiratory distress syndrome caused by other pulmonary conditions. A comparison of the controls (n = 20) and the COVID-19 patients (n = 20) revealed that the latter had a higher neutrophil count (median, 63.8% of the cell count) with lower percentages of macrophages and lymphocytes. An increase in the expression of CD68-positive, monocytic multinucleated giant cells (MGCs) was reported; megakaryocytes were not detected on CD61 staining. Perls staining showed isolated elements. In situ RNA analysis demonstrated scattered chromogenic signals in type II pneumocytes. An ultrastructural analysis confirmed the presence of intracytoplasmic vacuoles containing rounded structures measuring 140 nm in diameter (putative viral particles). In COVID-19 patients, the clinicopathological correlation revealed a positive correlation between lactate dehydrogenase values and MGCs (r = 0.54). The analysis of BAL samples might be implemented as a routine practice for the evaluation of COVID-19 patients in ICUs in the appropriate clinical scenario. Additional studies using a larger sample size of patients who developed COVID-19 during the second wave of the epidemic in the autumn of 2020 are needed to further support our findings.

Activation of PPG neurons following acute stressors differentially involves hindbrain serotonin in male rats

Neuropharmacology

2021 Feb 10

Leon, RM;Borner, T;Stein, LM;Urrutia, NA;De Jonghe, BC;Schmidt, HD;Hayes, MR;
PMID: 33581143 | DOI: 10.1016/j.neuropharm.2021.108477

Within the hindbrain, serotonin (5-HT) functions as a modulator of the central glucagon-like peptide-1 (GLP-1) system. This interaction between 5-HT and GLP-1 is achieved via 5-HT2C and 5-HT3 receptors and is relevant for GLP-1-mediated feeding behavior. The central GLP-1 system is activated by various stressors, activates the hypothalamic pituitary adrenocortical (HPA) axis, and contributes to stress-related behaviors. Whether 5-HT modulates GLP-1's role in the stress response in unknown. We hypothesized that the serotonergic modulation of GLP-1-producing neurons (i.e., PPG neurons) is stimuli-specific and that stressed-induced PPG activity is one of the modalities in which 5-HT plays a role. In this study, we investigated the roles of 5-HT2C and 5-HT3 receptors in mediating the activation of PPG neurons in the nucleus tractus solitarius (NTS) following exposure to three different acute stressors: lithium chloride (LiCl), noncontingent cocaine (Coc), and novel restraint stress (RES). Results showed that increased c-Fos expression in PPG neurons following LiCl and RES-but not Coc-is dependent on hindbrain 5-HT2C and 5-HT3 receptor signaling. Additionally, stressors that depend on 5-HT signaling to activate PPG neurons (i.e., LiCl and RES) increased c-Fos expression in 5-HT-expressing neurons within the caudal raphe (CR), specifically in the raphe magnus (RMg). Finally, we showed that RMg neurons innervate NTS PPG neurons and that some of these PPG neurons lie in close proximity to 5-HT axons, suggesting RMg 5-HT-expressing neurons are the source of 5-HT input responsible for engaging NTS PPG neurons. Together, these findings identify a direct RMg to NTS pathway responsible for the modulatory effect of 5-HT on the central GLP-1 system-specifically via activation of 5-HT2C and 5-HT3 receptors-in the facilitation of acute stress responses.

Implantation of regenerative complexes in traumatic brain injury canine models enhances the reconstruction of neural networks and motor function recovery

Theranostics

2021 Jan 01

Jiang, J;Dai, C;Liu, X;Dai, L;Li, R;Ma, K;Xu, H;Zhao, F;Zhang, Z;He, T;Niu, X;Chen, X;Zhang, S;
PMID: 33391504 | DOI: 10.7150/thno.50540

Rationale: The combination of medical and tissue engineering in neural regeneration studies is a promising field. Collagen, silk fibroin and seed cells are suitable options and have been widely used in the repair of spinal cord injury. In this study, we aimed to determine whether the implantation of a complex fabricated with collagen/silk fibroin (SF) and the human umbilical cord mesenchymal stem cells (hUCMSCs) can promote cerebral cortex repair and motor functional recovery in a canine model of traumatic brain injury (TBI). Methods: A porous scaffold was fabricated with cross-linked collagen and SF. Its physical properties and degeneration rate were measured. The scaffolds were co-cultured with hUCMSCs after which an implantable complex was formed. After complex implantation to a canine model of TBI, the motor evoked potential (MEP) and magnetic resonance imaging (MRI) were used to evaluate the integrity of the cerebral cortex. The neurologic score, motion capture, surface electromyography (sEMG), and vertical ground reaction force (vGRF) were measured in the analysis of motor functions. In vitro analysis of inflammation levels was performed by Elisa while immunohistochemistry was used in track the fate of hUCMSCs. In situ hybridization, transmission electron microscope, and immunofluorescence were used to assess neural and vascular regeneration. Results: Favorable physical properties, suitable degradation rate, and biocompatibility were observed in the collagen/SF scaffolds. The group with complex implantation exhibited the best cerebral cortex integrity and motor functions. The implantation also led to the regeneration of more blood vessels and nerve fibers, less glial fibers, and inflammatory factors. Conclusion: Implantation of this complex enhanced therapy in traumatic brain injury (TBI) through structural repair and functional recovery. These effects exhibit the translational prospects for the clinical application of this complex.

Correlation of tgfb2 mRNA expression to disease progression in a time course of chronic biliary liver disease

37. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber

2021 Jan 01

Albin, J;Meindl-Beinker, N;Ebert, M;Teufel, A;Dooley, S;Dropmann, A;
| DOI: 10.1055/s-0040-1721973

Question To identify the cellular source of TgfB2 in a time course of cholestatic liver disease using Abcb4-KO mice and PSC patients, and to correlate findings to disease stages. Methods Liver samples from PSC liver biopsies and Abcb4-KO mice at the age of 2-, 6-, 8- and 12-months were stained for HE, Sirius Red and Orcein to visualize inflammation and fibrosis. Morphological evaluation was performed using Ishak and Nakanuma scoring systems. Tgfb2 mRNA expression was analysed by in situ hybridisation using the RNAscope technique and then compared to age matched wildtype Balb/c mice and disease-free human liver as well as PSC samples. Results In Abcb4-KO tissues, we found an increase in grade and stage of fibrosis and inflammation with advancing disease progression using both scoring systems in comparison to wild type mice. Disease progression was faster in female than in male mice, especially with regard to inflammation. Subscores, e.g. portal tract inflammation and interface hepatitis increased first, while confluent necrosis occurred not before the age of 12 months. Tgfb2 mRNA was expressed in areas of proliferating bile ducts and fibrotically rearranged tissue at all stages of cholestatic disease. Both murine and human livers showing higher Ishak and Nakanuma scores also showed stronger tgfb2 expression, particularly in samples with a high grade of portal inflammation. We are currently performing costaining with cell type/cell fate markers to specifically identify the cell type that upregulates TGFb2 expression. Conclusions The expression of tgfb2 mRNA increased with disease progression of Abcb4-KO mice, whereby prominent inflammatory grades present with the highest expression levels in mice and human.

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload.

J Mol Cell Cardiol. 2019 Jan 3.

2019 Jan 03

Satoh M, Nomura S, Harada M, Yamaguchi T, Ko T, Sumida T, Toko H, Naito AT, Takeda N, Tobita T, Fujita T, Ito M, Fujita K, Ishizuka M, Kariya T, Akazawa H, Kobayashi Y, Morita H, Takimoto E, Aburatani H, Komuro I.
PMID: 30611794 | DOI: 10.1016/j.yjmcc.2018.12.018

Abstract BACKGROUND: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure. METHODS AND RESULTS: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes. CONCLUSIONS: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.

Mouse Brain Regions Activated By Isoflurane Anesthesia Marked By C-Fos Labeling

The Journal of Pain

2023 Apr 01

Yuan, M;Zhao, J;McGinnis, A;Mathew, J;Wang, F;Ji, R;
| DOI: 10.1016/j.jpain.2023.02.115

Although anesthesia is commonly used in the fields of medicine and scientific research, the neural mechanisms and circuits through which it produces analgesia is still unclear. Utilizing c-fos labeling of neuronal activity, this project aimed to investigate the brain regions of C57BL/6 mice, which become activated subsequent to isoflurane anesthesia. RNAscope in situ hybridization was used to examine c-fos mRNA activation in the brain. Confocal microscopy was utilized to locate and characterize brain regions displaying c-Fos activation. Finally, manual quantification of c-fos activation in identified brain regions was conducted through Fiji software. The brain regions identified resemble brain areas that have been associated with pain regulation in literature, including the central nucleus of amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), centrally-projecting Edinger-Westphal nucleus (EWcp), piriform cortex (PC), and para-supraoptic nucleus (ParaSON). Furthermore, the CeA displayed the greatest average number of positive cells and the densest activation, supporting its importance in pain and analgesia. The identified brain regions validate the prominent findings of prior studies, which also found c-Fos activation subsequent to isoflurane anesthesia in the CeA, PVN, and ParaSON (Hua et al., Nat Neurosci, 2020). New regions of c-fos activation, including the EWcp and PC, found in this study are in need of further exploration. PC activation may also be caused by smell from isoflurane. The connections and coordination which the identified brain regions have in producing analgesia is also an area for future investigation. This study is supported by Duke University Anesthesiology Fund and NIH grant R01-DE29342. This study is supported by Duke University Anesthesiology Fund and NIH grant R01-DE29342.

Effect of diabetic foot ulcers and other risk factors on the prevalence of lower extremity amputation: A meta-analysis

International wound journal

2023 Apr 24

Zhang, H;Huang, C;Bai, J;Wang, J;
PMID: 37095728 | DOI: 10.1111/iwj.14179

A meta-analysis study was conducted to measure the consequence of diabetic foot ulcers (DFUs) and other risk factors (RFs) on the prevalence of lower extremity amputation (LEA). A comprehensive literature inspection till February 2023 was applied and 2765 interrelated studies were reviewed. Of the 32 chosen studies enclosed, 9934 subjects were in the chosen studies' starting point, and 2906 of them were with LEA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of DFUs and other RFs on the prevalence of LEA by the continuous and dichotomous approaches and a fixed or random effect model. Male gender (OR, 1.30; 95% CI, 1.17-1.44, P < .001), smoking (OR, 1.24; 95% CI, 1.01-1.53, P = .04), previous foot ulcer (OR, 2.69; 95% CI, 1.93-3.74, P < .001), osteomyelitis (OR, 3.87; 95% CI, 2.28-6.57, P < .001), gangrene (OR, 14.45; 95% CI, 7.03-29.72, P < .001), hypertension (OR, 1.17; 95% CI, 1.03-1.33, P = .01), and white blood cells count (WBCC) (MD, 2.05; 95% CI, 1.37-2.74, P < .001) were significantly shown to be an RF in LEA in subjects with DFUs. Age (MD, 0.81; 95% CI, -0.75 to 2.37, P = .31), body mass index (MD, -0.55; 95% CI, -1.15 to 0.05, P = .07), diabetes mellitus type (OR, 0.99; 95% CI, 0.63-1.56, P = .96), and glycated haemoglobin (MD, 0.33; 95% CI, -0.15 to 0.81, P = .17) were not shown to be an RF in LEA in subjects with DFUs. Male gender, smoking, previous foot ulcer, osteomyelitis, gangrene, hypertension, and WBCC were significantly shown to be an RF in LEA in subjects with DFUs. However, age and diabetes mellitus type were not shown to be RF in LEA in subjects with DFUs. However, caused of the small sample sizes of several chosen studies for this meta-analysis, care must be exercised when dealing with its values.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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