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Few reports about successful forefoot replantation in children have been published. In this article, we present a case of a 3-year-old boy with severe complete amputation of the left forefoot from a crushed and degloved injury in a motorcycle accident. The replantation was successfully performed, even though total ischemia time lasted 8 hours, of which 4 hours was cold ischemia time. The child was able to walk without significant difficulties from 4 months postoperatively and led a normal life in school at 2 years of follow-up. In this case, we present the replantation of a high-velocity traumatic partial foot amputation in a child with excellent function and cosmetic outcome.

Gd(III) containing wastewater has toxic effects on both public health and aquatic life. However, few literature is available using wastes biomass containing cellulose with enough high adsorption capacity to remove Gd(III). Herein, we described a facile synthesis of triazole and carboxyl- functionalized magnetic cellulose-based material from ramie stalk (TCM-RS) through click chemistry strategy for the first time. The synthesized sample (TCM-RS) was used as an efficient adsorbent for the removal of Gd(III) from aqueous solution. The obtained materials were well characterized. Batch adsorption experiments showed that the combination of bifunctional chelating ligand, sufficient specific surface area, and magnetic response endowed the adsorbent with excellent adsorption selectivity, high adsorption capacity and easy separation of adsorbent from solutions, respectively. The maximum Gd(III) uptake of TCM-RS (62.8 mg/g) was reached within 40 min. Adsorption isotherms and kinetics revealed that the Langmuir model and the pseudo-second-order kinetics model could well describe the adsorption process of Gd(III) onto TCM-RS. Moreover, the sorbent can be regenerated and reused for five cycles without significant loss in adsorption capacity. Our study not only provides new insights into the fabrication of TCM-RS through click chemistry strategy, but also reveal that TCM-RS has great potential application for the removal of Gd(III) from wastewater.

Gadolinium is known to be a most widely used but toxic rare-earth element, and Gd(III) ions exist in aqueous media will bring about serious damage to the ecosystem. However, few work on the application of adsorption strategy with enough high Gd(III) uptake is reported. Since the hollow mesoporous silica nanospheres (HMSNs) and amino-phosphonic acid (APA) compounds have shown inherent advantage for being used as effective adsorbent and chelating ligand in toxic metals adsorption due to their remarkable properties. Herein, we follow the cleaner production philosophy, proposing for the first time to modify the HMSNs nanomaterial with APA group by reacting phosphorous acid with cyano-functionalized hollow mesoporous SiO2 (CFHMSNs) via one-step reaction under solvent-free conditions, and apply to remove Gd(III) form wastewater. The obtained materials are characterized by a variety of techniques. Characterization results show that the APA-functionalized material (AFHMSNs) has ordered mesoporous structure, high stability and large surface area (825.3 m2/g). The maximum uptake of Gd(III) for AFHMSNs (387.3 mg/g) is much higher than those of the reported adsorbents because of the high surface area, and multifunctional chelating interactions of the adsorbent with Gd(III) ions. Gd(III) adsorption onto AFHMSNs can be well described by the Langmuir isotherm and pseudo second order kinetics model. The adsorption is chemical complexation mechanism which is proposed based on FTIR and XPS analysis. It is found for the first time that the adsorption of Gd(III) onto AFHMSNs slightly enhanced with the coexistence of Al3+ in the relatively lower concentrations, which may be due to the synergistic effect of pseudo-boehmite. This work provides a favorable strategy to design and synthesis of hollow mesoporous nanomaterial with superior adsorption performances and potential for the cleanup of toxic metals from wastewater.

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule RORγt activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17–blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.

Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4(+)CD146(+)CCR5(+) T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4(+)CD146(+)CCR5(+) T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4(+)CD146(+)CCR5(+) T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA-transduced human T cells. Furthermore, the frequency of CD4(+)CD146(+)CCR5(+) Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT. CA extern

During cancer development, tumor suppressor genes were silenced by promoter methylation or histone deacetylation. Histone deacetylases (HDACs) are important to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed as a new therapeutic approach to cancer. The current study aims to understand the effect and molecular mechanisms of HDACis on gastric cancer cells. Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric cancer cells. PUMA was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. Patients with low PUMA expression had significant decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression inhibited the growth of gastric cancer cells while PUMA depletion promoted cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 expression but promoted the interaction of p53 with PUMA promoter. In summary, proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression level is a valuable prognosis factor for gastric cancer. HDAC3 is important to downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In combination with chemotherapy, targeting HDAC3 might be a promising strategy to induce apoptosis of gastric cancer cells.

GVHD of the gastrointestinal tract (GI) is associated with high mortality. We have identified systemic, skin- and GI-specific plasma biomarkers present at clinical GVHD onset, and more recently biomarkers for treatment responsiveness. However, in order to identify early GI-specific biomarkers prior to GVHD onset, we performed state-of-the-art proteomics on plasma samples taken 14 days prior to clinical manifestation of GI GVHD. We selected candidates that were increased at least 1.5 fold in plasma from GI GVHD patients compared to HSCT patients without GVHD at matched time points. We identified two lead proteins: CD146, a cell adhesion and trafficking molecule expressed on a subset of CD4+ T cells and endothelial cells, and the chemokine (C-C motif) ligand 14 that binds to the chemokine receptor CCR5 on T cells. As these proteins have not been previously identified in proteomics experiments and antibodies for their corresponding receptors on T cells were available, we analyzed their expression profiles on PB cells from 214 HSCT patients (71 GI GVHD, 48 no GVHD, 33 non-GVHD enteritis, 22 skin first GVHD, 40 isolated skin GVHD) at the onset of symptoms. The frequency of CD146+CCR5+ T cells was significantly increased in GI GVHD patients compared to patients without GVHD, non-GVHD enteritis, or with isolated skin GVHD, as well as increased in patients who first experienced skin and then GI GVHD (Fig. 1). When using the median % of CD146+CCR5+ T cells detected in GI GVHD patients to classify patients into low and high-risk groups, patients in the high-risk group had higher 6-month non-relapse mortality (42 vs. 20%, p = 0.02). Importantly, CD146+CCR5+ T cells at onset of clinical symptoms were not correlated with GI histologic severity, suggesting that these cells are not mucosa damage products but rather systemic effectors. Thus, we measured their frequencies in samples taken at a median of 19 days post-transplant and with a median interval of 14 days prior to clinical symptoms and found that CD146+CCR5+ T cells circulate in patients before GI GVHD clinical onset. In GI GVHD patients, these cells expressed a Th1 and Th17 phenotype and expressed high levels of the activation marker ICOS known to be critical for the development of human Th17 cells. To test the hypothesis that CD146+ T cells are Th17-prone, we next investigated whether in vitro polarization of CD4 T cells with defined stimulation conditions will increase the CD146+CCR5+ expression as well as the production of Th1 and Th17 cytokines. Fig. 2A demonstrates that CD4 T cells differentiated with both Th17-inducing cytokines and ICOS co-stimulation had a significantly higher percentage of CD146+CCR5+ T cells and co-expressed more IL-17A+IFNγ+ than T-cells stimulated with Th1-inducing cytokines or by CD28. We then analyzed colonic mucosa biopsies from patients with GI GVHD (N = 18) and non-GVHD enteritis (N = 10) for the expression of CD146 by immunohistochemistry. CD146 expression was detected on CD3 lymphoid cells and was strongly present on the endothelium. The CD146+ vessel count in GI GVHD tissues was significantly higher than in non-GVHD enteritis tissues (p < 0.001). Th17 cells migrated more efficiently through endothelial cell monolayers than their Th1 counterparts (Fig. 2B). Lentivirus-mediated shRNA knock-down of CD146 in either cell type demonstrated that reduced CD146 expression on CD4+ T cells, but not on endothelial cells significantly reduced the T-cell transendothelial migration (Fig. 2C), suggesting that CD146 on T cells is paramount for promoting infiltration of pathogenic T cells into GVHD target organs. As proof of principle for this hypothesis, we tested donor CD146-/- T cells in an allogeneic murine GVHD model and did not find any difference in GVHD severity when compared to wild type CD146+/+ T cells. Finally, we used a xenogeneic GVHD mouse model with injection of human CD4+ T cells lentivirally transduced with CD146 or control shRNA. In comparison to the vector control group, mice transplanted with CD146 shRNA transduced T cells did not lose weight (Fig. 3A), had similar human T cells engraftment (B), had less splenic CD146+CCR5+ T cells (C), and expressed less TBET 53 days after transplant (D). In conclusion, early quantification of a novel CD146+CCR5+ Th17-prone and ICOS-induced population may allow identification of patients at risk for GI GVHD development and subsequent mortality. Targeting CD146 may represent a new avenue to treat GVHD. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.