Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

IL-34, the rationale for its expression in physiological and pathological conditions.

IL-34 is a cytokine that shares one of its receptors with CSF-1. It has long been thought that CSF-1 receptor (CSF-1R) receives signals only from CSF-1, but the identification of IL-34 reversed this stereotype. Regardless of low structural homology, IL-34 and CSF-1 emanate similar downstream signaling through binding to CSF-1R and provoke similar but different physiological events afterward. In addition to CSF-1R, protein-tyrosine phosphatase (PTP)-ζ and Syndecan-1 were also identified as IL-34 receptors and shown to be at play. Although IL-34 expression is limited to particular tissues in physiological conditions, previous studies have revealed that it is upregulated in several diseases. In cancer, IL-34 is produced by several types of tumor cells and contributes to therapy resistance and disease progression. A recent study has demonstrated that tumor cell-derived IL-34 abrogates immunotherapy efficacy through myeloid cell remodeling. On the other hand, IL-34 expression is downregulated in some brain and dermal disorders. Despite accumulating insights, our understanding of IL-34 may not be even close to its nature. This review aims to comprehensively describe the physiological and pathological roles of IL-34 based on its similarity and differences to CSF-1 and discuss the rationale for its disease-dependent expression pattern.

Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells.

For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts.

Early and Midterm Outcomes of Chimney Endovascular Aortic Repair for Ruptured Abdominal Aortic Aneurysms.

PURPOSE: To compare the outcomes of endovascular aortic aneurysm repair using a chimney technique (ch-EVAR) with those of the standard EVAR (st-EVAR) for ruptured abdominal aortic aneurysms (RAAA). MATERIALS AND METHODS: We implemented ch-EVAR for juxtarenal RAAA based on obvious anatomical indications after converting the strategy for RAAA from open repair to EVAR. A retrospective, cohort-based study was conducted on patients with RAAA who were treated using EVAR in our hospital between July 2011 and March 2022. EVAR cases were extracted, and outcomes were compared between ch-EVAR and st-EVAR. Patient clinical status, anatomical variables, treatment, and follow-up data were evaluated. RESULTS: A total of 56 (82%) and 12 (18%) patients were treated by st-EVAR and ch-EVAR, respectively. Thirty-day mortality rates were comparable between the 2 groups [8.9% in st-EVAR vs 8.3% in ch-EVAR (p= 0.95)]. Short-term outcomes showed that no type Ia endoleak occurred in either group. Midterm outcomes, including sac enlargement [7.5% in st-EVAR vs 0% in ch-EVAR (p= 0.37)], shrinkage [77.5% in st-EVAR vs 80.0% in ch-EVAR (p= 0.86)], and overall survival and freedom from aneurysm-related reintervention at 3 years [64.7% and 96.4% in the EVAR group vs 91.7% and 100% in the ch-EVAR group, respectively (p= 0.30 and 0.52)], were not significantly different between the 2 groups. CONCLUSION: Ch-EVAR for RAAA showed remarkably excellent outcomes, comparable to those of st-EVAR. Ch-EVAR is considered technically feasible in experienced centers. The indications for EVAR for RAAA may be further expanded using the chimney technique, resulting in overall improved outcomes for RAAA. CLINICAL IMPACT: This is a retrospective, single-center analysis of 68 patients with ruptured abdominal aortic aneurysms (RAAAs) treated by endovascular repair (EVAR) to investigate the efficacy of the chimney technique for juxtarenal RAAA. Thirty-day mortality rate was 8.3% for the chimney EVAR group, which was equivalent to that in the standard EVAR group. Mid-term outcomes including sac enlargement/shrinkage, overall survival, and freedom from aneurysm-related reintervention were comparable between the two groups. This report suggests the possibility of broadening the selection criteria of the current endovascular strategy using the chimney technique.

The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance.

In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation.

TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival.

The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies. Here, we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to that of 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.

[Two Cases of Chemotherapy after Self-Expandable Metallic Stent Placement for Obstructive Sigmoid Cancer with Unresectable Liver Metastasis].

Immediate decompression and induction of chemotherapy are exceedingly critical for obstructive colorectal cancer patients with unresectable liver metastasis. Systematic chemotherapy was administered after self-expandable metallic stent(SEMS) placement in 2 patients with obstructive sigmoid cancer with unresectable liver metastasis. Chemotherapy-induced tumor shrinkage led to SEMS migration, enabling the use of an anti-VEGF drug. Eventually, both patients underwent successful management without restenosis.

[A Case of Resection of Para-Aortic Lymph Node Recurrence following Rectal Cancer Surgery].

A 54-year old man diagnosed with rectal cancer underwent laparoscopic high anterior resection with Japanese D3 lymph node dissection. The pathology results were as follows: pT2pN3M0, pStage Ⅲb(Japanese Classification of Colorectal, 8th edition). Adjuvant chemotherapy with CapeOX regimen was administered 8 courses. 1.5 years after the operation, computed tomography(CT)examination revealed a swollen para-aortic lymph node(PALN). Positron emission tomography (PET)-CT revealed PALN with high FDG uptake. We considered that neo-adjuvant chemotherapy and PALN dissection may be possible for PALN, which was isolated metastasis and curative by surgery. After 6 courses of bevacizumab-FOLFIRI therapy was administered, PALN dissection was performed. Pathological examination of the resected specimen showed adenocarcinoma in 4 of the 16 dissected lymph nodes. Histological treatment effect of preoperative therapy was Grade 1b. Postoperatively 6 courses of FOLFIRI were administered. The patient has been followed up for 7 years and 8 months after the first surgery, 5 years and 9 months after the curative resection, with no recurrence showed complete cure. Multidisciplinary treatment with anticancer drug and R0 resection was an effective treatment for isolated PALN recurrence of rectal cancer.

Endovascular Aneurysm Repair With Inferior Mesenteric Artery Embolization for Preventing Type II Endoleak: A Prospective Randomized Controlled Trial.

OBJECTIVE: This study aimed to evaluate the effect of inferior mesenteric artery (IMA) embolization during endovascular aneurysm repair (EVAR) in patients at high risk of type II endoleak (T2EL) in randomized controlled trial (RCT). SUMMARY BACKGROUND DATA: Several studies have demonstrated a reduction of T2EL by IMA embolization before EVAR. However, there have been no RCT confirming the efficacy of IMA embolization. METHODS: Patients scheduled for elective EVAR between April 2014 and March 2018 were eligible. Patients at high risk of T2EL (IMA patency with IMA ≥3 mm, LAs ≥2 mm, or an aortoiliac-type aneurysm) were prospectively randomized to receive EVAR with or without IMA embolization. The primary endpoint was occurrence of T2EL during follow-up. Secondary endpoints included aneurysmal sac changes, adverse events from IMA embolization, and reintervention rate due to T2EL. This trial is registered with the University Hospital Medical Information Network, number UMIN000022147. RESULTS: One hundred thirteen patients had high risk and 106 were randomized. In the intention-to-treat analysis, the incidence of T2EL was significantly lower in the embolization group [24.5% vs 49.1%; P = 0.009, absolute risk reduction = 24.5%; 95% confidence interval (CI), 6.2-40.5, number needed to treat = 4.1; 95% CI, 2.5-16.1]. The aneurysmal sac shrunk significantly more in the embolization group (-5.7 ±â€Š7.3 mm vs -2.8 ±â€Š6.6 mm; P = 0.037), and the incidence of aneurysmal sac growth related to T2EL was significantly lower in the embolization group (3.8% vs 17.0%; P = 0.030). There were no complications related to IMA embolization or reinterventions associated with T2EL. CONCLUSIONS: Our results demonstrated the effectiveness of IMA embolization during EVAR in high-risk patients for the prevention of T2EL, which is suggested for avoiding aneurysmal sac enlargement related to T2EL.

Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). METHODS: The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). RESULTS: The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). CONCLUSIONS: The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

[A Case of Advanced Gastric Cancer with Multiple Liver Metastases Treated with Curative Conversion Therapy after S-1 plus CDDP].

A57 -year-old man was diagnosed with advanced gastric cancer(adenocarcinoma[tub2/por1])with multiple(S3, S4, S5, S6, S8)liver and para-aortic lymph node metastases. The tumor was classified as cT4a, N3, M1, HEP, cStage IV, and the patient received chemotherapy with S-1 plus CDDP(SP). After 10 courses of SP, a CT scan revealed that the primary tumor and the metastases disappeared. The patient presented with cCR and underwent distal gastrectomy, D2 lymph node dissection, partial hepatic resection, and cholecystectomy. The histological diagnosis was classified as ypT0N0M0,(ypStage 0), pCR, and pathological Grade 3.

Enhancement of Nitric Oxide Production Is Responsible for Minimal Intimal Hyperplasia of Autogenous Rabbit Arterial Grafts.

BACKGROUND: Vascular endothelium induces smooth muscle cell (SMC) relaxation mainly mediated by endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF). It has previously been reported that functions of these endothelium factors have been greatly impaired in vein grafts. The present study was undertaken to determine whether the functions of EDNO and EDHF might be altered in artery graft.Methods and Results:In rabbits, the right carotid artery was excised and implanted in its original position as an autogenous graft ("artery graft") and the non-operated left carotid artery served as the "control artery". Histochemical changes, acetylcholine (ACh)-induced effects on the intracellular concentration of Ca2+([Ca2+]i) in endothelial cells, endothelium-dependent SMC hyperpolarization and relaxation, and tissue cGMP content were examined on post-operative day 28. "Artery graft" displayed a minimal amount of intimal hyperplasia. When compared with the "control artery", it exhibited greater ACh-induced, endothelium-dependent relaxation, but the reverse was true when EDNO production was blocked. In the "artery graft" (vs. the "control artery"), basal cGMP content was greater, whereas the [Ca2+]iincrease in endothelial cells and the endothelium-dependent SMC-hyperpolarization induced by ACh were less. CONCLUSIONS: It is suggested that the [Ca2+]i-independent EDNO production covers the loss of function of endothelium-dependent SMC hyperpolarization and minimizes intimal hyperplasia caused by surgical operation in autogenous carotid artery graft.

[Sixteen Cases of Colon Stenting as a Bridge to Surgery(BTS)for Obstructive Colorectal Cancer].

INTRODUCTION: Colonic stent insertion is widely used as a bridge to surgery(BTS)for obstructive colorectal cancer. Stenting can shorten hospitalization and decrease complication and colostomy rates in comparison with emergency surgery. We investigated patients who underwent colonic stent insertion for BTS in our hospital. PATIENTS: Sixteen patients(8 men, 8 women) with a colorectal obstruction score of 0 or 1 who underwent colonic stent insertion as a BTS between April 2015 and April 2017 period were investigated. RESULTS: Mean patient age was 68.2(45-94)years. Technical success was obtained in all patients, and clinical success in 14(87%). Total colonoscopy was possible via stent in 10 patients. Nine patients were temporarily discharged from the hospital, and median time to operation was 18(2-43)days. Laparoscopic resection was performed in 14 patients, and anastomotic leakage was a postoperative complication in 1 patient. Colostomy was performed in only 1 patient with anastomotic leakage. CONCLUSION: Good results were obtained with careful patient selection and safe colonic stent insertion.

Dipeptidyl peptidase 4 inhibitor reduces intimal hyperplasia in rabbit autologous jugular vein graft under poor distal runoff.

BACKGROUND: Dipeptidyl peptidase 4 inhibitors are widely used in patients with type 2 diabetes mellitus to accomplish glycemic control through an increase in the blood glucagon-like peptide 1 (GLP-1) concentration. These agents also inhibit vascular inflammation (eg, in atherosclerosis). This study was undertaken to determine whether and how vildagliptin (a potent dipeptidyl peptidase 4 inhibitor) might reduce intimal hyperplasia in vein grafts. METHODS: Twelve rabbits were randomly divided into two groups; one group received vildagliptin orally (10 mg/kg/d; n = 6), whereas the control group (n = 6) did not. Vildagliptin administration was started 7 days before rabbits underwent interposition reversed autologous jugular vein grafting and ended at graft harvesting (28 days after the operation). Histochemical changes in the vascular wall were examined, as were changes in the acetylcholine-induced effects on the endothelial Ca(2+) concentration ([Ca(2+)]i) and endothelium-dependent relaxation. RESULTS: Under fasting conditions, vildagliptin increased the plasma GLP-1 concentration, without affecting plasma glucose or insulin. Acetylcholine induced endothelium-dependent relaxation only in the vildagliptin group, and this was blocked by the nitric oxide synthase inhibitor N(ω)-nitro-l-arginine. Acetylcholine did not modify the endothelial [Ca(2+)]i in either the control or vildagliptin group. Intimal hyperplasia was significantly less in the vildagliptin group (0.11 ± 0.02 mm, n = 5) than in the controls (0.31 ± 0.06 mm, n = 4; P < .01). CONCLUSIONS: Vildagliptin increased the plasma GLP-1 concentration. It also enhanced acetylcholine-induced [Ca(2+)]i-independent endothelial nitric oxide release and reduced vein graft intimal hyperplasia, independently of any glycemic control action.

Selenate adsorption on pre-coordinated Fe3+-silane complexes grafted on mesoporous silicas.

Fe3+ was coordinated N-[2-(aminoethyl)-3-aminopropyltriethoxysilane], AEAPTES, followed by being grafted on MCM-41, SBA-15 and Cab-O-sil M7D. The mixing ratio, n = [AEAPTES]/[Fe], in the above coordination reaction was varied from 1 to 3. These nine functionalized silicas, denoted as Fe(en)n-silica (n = 1, 2, 3 and silica = MCM-41, SBA-15 and M7D), were used for the adsorption of aqueous selenate. The saturation of adsorption isotherm occurred at Se/Fe = 2 on Fe(en)2- MCM-41 and Fe(en)2-SBA-15, while Fe(en)- and Fe(en)3-MCM-41 and Fe(en)- and Fe(en)3-SBA-15 adsorbed selenate until Se/Fe = 1. The saturation at Se/Fe = 1 was obtained for all absorbents prepared with M7D substrate, suggesting a transformation of the adsorption sites realized on Fe(en)2-MCM-41 and Fe(en)2-SBA-15. The concave curvature of the surface of mesoporous silicas is possibly critical to retain the coordination structure of adsorption sites. The largest capacity obtained among these adsorbents was 1.1 mmol/g, found on Fe(en)2-SBA-15. The structure of adsorption sites was analysed by X-ray absorption spectroscopies in order to obtain the evidences for the distortion of coordination structure induced by grafting and the bond formation between Se and Fe after adsorption.

Grafting of precoordinated Cu(2+)-N-(2-aminoethyl)aminopropylsilane complexes onto mesoporous silicas and the adsorption of aqueous selenate on them.

N-(2-Aminoethyl)aminopropylsilane (AeAptes) was coordinated with Cu(2+) with Cu:AeAptes ratios of 1:1 and 1:2. These were then grafted onto MCM-41 [the products being denoted as Cu(en)-MCM-41 and Cu(en)2-MCM-41, respectively] and SBA-15 [the products being denoted as Cu(en)-SBA-15 and Cu(en)2-SBA-15, respectively]. The periodic structures of these mesoporous silica frameworks were well-retained after grafting. UV-visible and EPR spectroscopies were used to analyze the coordination structure of Cu(2+), revealing the structure expected from the ratio of Cu(2+) to silane. We also prepared Cu(en)- and Cu(en)2-M7D by the same procedure using Cab-O-sil M7D silica. In contrast to the complexes grafted onto the mesoporous silicas, no significant differences were found in the d-d transition band positions, the g-tensor, and hyperfine coupling constants between Cu(en)-M7D and Cu(en)2-M7D. The structural parameters of these were almost the same as those of Cu(en)-MCM-41 and Cu(en)-SBA-15, suggesting that the grafting onto M7D resulted in the transformation of coordination structure of Cu(2+)(AeAptes)2. The adsorption of selenate was analyzed using the Langmuir equation. The adsorption capacities for Cu(en)- and Cu(en)2-mesoporous silicas were Se/Cu = 0.5 and 1.0, respectively, while the Langmuir coefficients for Cu(en)2-mesoporous silicas were more than twice those for Cu(en)-mesoporous silicas. However, no significant differences in these two parameters were found between Cu(en)- and Cu(en)2-M7D; Se/Cu = 0.53-0.56 at saturation and the Langmuir coefficients were the same. The decomposition of the coordinated Cu complex after grafting onto M7D is discussed with respect to the structure of the silica surface. The electronic state of Cu in Cu(en)- and Cu(en)2-mesoporous silicas was analyzed by XANES spectroscopy before and after the adsorption of selenate.

A mechanism of IL-34-induced resistance against cytotoxic anti-cancer therapies such as radiation by X-ray and chemotherapy by Oxaliplatin.

Interleukin-34 (IL-34) has been known as a factor that is involved with tumor progression and therapeutic resistance. However, there are limitations to addressing the mechanism of how IL-34 induces therapeutic resistance. Here, we show a mechanism of IL-34-induced resistance against cytotoxic anti-cancer therapies such as radiotherapy using X-ray and chemotherapy by Oxaliplatin. This research demonstrates that IL-34 immunologically changes the tumor microenvironment after treatments with radiation or chemotherapeutic agents such as oxaliplatin. We identified the changes in immune cells using flow cytometry and immunofluorescent (IF) staining, which are up-regulated upon the existence of IL-34. Overall, these findings demonstrate the possibility of IL-34 blockade as a novel combination therapy for cancer.