Thioredoxin A of Streptococcus suis Serotype 2 Contributes to Virulence by Inhibiting the Expression of Pentraxin 3 to Promote Survival Within Macrophages.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that can infect humans in contact with infected pigs or their byproducts. It can employ different types of genes to defend against oxidative stress and ensure its survival. The thioredoxin (Trx) system is a key antioxidant system that contributes adversity adaptation and pathogenicity. SS2 has been shown to encode putative thioredoxin genes, but the biological roles, coding sequence, and underlying mechanisms remains uncharacterized. Here, we demonstrated that SSU05_0237-ORF, from a clinical SS2 strain, ZJ081101, encodes a protein of 104 amino acids with a canonical CGPC active motif and an identity 70-85% similar to the thioredoxin A (TrxA) in other microorganisms. Recombinant TrxA efficiently catalyzed the thiol-disulfide oxidoreduction of insulin. The deletion of TrxA led to a significantly slow growth and markedly compromised tolerance of the pathogen to temperature stress, as well as impaired adhesion ability to pig intestinal epithelial cells (IPEC-J2). However, it was not involved in H2O2 and paraquat-induced oxidative stress. Compared with the wild-type strain, the ΔTrxA strain was more susceptible to killing by macrophages through increasing NO production. Treatment with TrxA mutant strain also significantly attenuated cytotoxic effects on RAW 264.7 cells by inhibiting inflammatory response and apoptosis. Knockdown of pentraxin 3 in RAW 264.7 cells was more vulnerable to phagocytic activity, and TrxA promoted SS2 survival in phagocytic cells depending on pentraxin 3 activity compared with the wild-type strain. Moreover, a co-inoculation experiment in mice revealed that TrxA mutant strain is far more easily cleared from the body than the wild type strain in the period from 8-24 h, and exhibits significantly attenuated oxidative stress and liver injury. In summary, we reveal the important role of TrxA in the pathogenesis of SS2.

Biomechanical Responses of Different Cap Thicknesses of Corneas After Small Incision Lenticule Extraction: Finite Element Analysis.

Purpose: This study analyzed the biomechanical responses of different corneal cap thicknesses after small incision lenticule extraction (SMILE). Methods: Individual finite element models of myopic eyes were constructed based on the clinical data. Then, four types of corneal cap thicknesses after SMILE were included for each model. The biomechanical effects of material parameters and intraocular pressure on corneas with different cap thicknesses were analyzed. Results: When the cap thickness increased, the vertex displacements of the anterior and posterior corneal surfaces decreased slightly. The corneal stress distributions demonstrated little change. Regarding wave-front aberrations caused by the displacements of the anterior surface, the absolute defocus value decreased slightly, but the magnitude of primary spherical aberration increased slightly. The horizontal coma increased, and the levels of other low-order and high-order aberrations were small and demonstrated little change. The corneal vertex displacement and wave-front aberration were significantly affected by elastic modulus and intraocular pressure, whereas the corneal stress distribution was greatly affected by intraocular pressure. There were obvious individual differences in the biomechanical responses of human eyes. Conclusions: The biomechanical difference of different corneal cap thicknesses after SMILE was small. The effect of corneal cap thickness was significantly less than that resulting from material parameters and intraocular pressure. Translational Relevance: Individual models were constructed based on the clinical data. The elastic modulus was controlled by programming to simulate its heterogeneous distribution in the actual human eye. The simulation was improved to bridge the gap between basic research and clinical care.

Wavefront aberrations caused by biomechanical effects after Small Incision Lenticule Extraction (SMILE) based on finite element analysis.

To examine wavefront aberrations induced by biomechanical effects after Small Incision Lenticule Extraction (SMILE) surgery. The three-dimensional (3D) finite element models of the human eye were established. By loading the intraocular pressure (IOP), the displacement of the anterior and posterior surface of the cornea was calculated. Then the displacement was converted into the wavefront aberrations by wave-surface fitting. The results showed that the induced wavefront aberrations were noticeable from biomechanical effects after SMILE surgery. The induced higher-order aberrations from the anterior corneal surface included spherical aberration, y-Trefoil, and x-Tetrafoil. Spherical aberration was positively correlated with corrected diopter (D), but x-Tetrafoil and y-Trefoil remained stable. The induced wavefront aberrations from the posterior corneal surface were smaller than those from the anterior corneal surface, and some of the aberrations compensated each other. With IOP increased, defocus and x-Tetrafoil from the anterior corneal surface increased, while y-Trefoil and spherical aberration decreased. The IOP only affected defocus from the posterior corneal surface. In addition, the incision size also had a distinct impact on primary x-astigmatism and x-Trefoil from the anterior corneal surface, and it had a smaller effect on the aberrations from the posterior corneal surface. Therefore, the biomechanical effects increased residual wavefront aberrations after SMILE refractive surgery.

Evolution of Graves' Disease during Immune Reconstitution following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation in a Boy Carrying Germline SAMD9L and FLT3 Variants.

Graves' disease, characterized by hyperthyroidism resulting from loss of immune tolerance to thyroid autoantigens, may be attributable to both genetic and environmental factors. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a means to induce immunotolerance via an artificial immune environment. We present a male patient with severe aplastic anemia arising from a germline SAMD9L missense mutation who successfully underwent HSCT from his HLA-haploidentical SAMD9L non-mutated father together with nonmyeloablative conditioning and post-transplant cyclophosphamide at 8 years of age. He did not suffer graft-versus-host disease, but Graves' disease evolved 10 months post-transplant when cyclosporine was discontinued for one month. Reconstitution of peripheral lymphocyte subsets was found to be transiently downregulated shortly after Graves' disease onset but recovered upon antithyroid treatment. Our investigation revealed the presence of genetic factors associated with Graves' disease, including HLA-B*46:01 and HLA-DRB1*09:01 haplotypes carried by the asymptomatic donor and germline FLT3 c.2500C>T mutation carried by both the patient and the donor. Given his current euthyroid state with normal hematopoiesis, the patient has returned to normal school life. This rare event of Graves' disease in a young boy arising from special HSCT circumstances indicates that both the genetic background and the HSCT environment can prompt the evolution of Graves' disease.

Peri-treatment adverse events of primary mediastinal non-seminomatous germ cell tumors.

Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) are rare but life-threatening thoracic cancers. We report our experience from eight patients with peri-treatment adverse events. By analyzing changes in tumor extent, serum tumor markers, and pathologies between diagnosis and transfer, those events could be attributed to postbiopsy respiratory insufficiency, growing teratoma syndrome, secondary histiocytic malignancy, and PMNSGCT progression. Subjecting patients to respiratory therapy, conventional or high-dose chemotherapy, and surgery controlled the disease, with five of the eight patients surviving disease free. These outcomes indicate that integrated appropriate and timely approaches are important in tackling peri-treatment adverse events.

Wave front aberrations induced from biomechanical effects after customized myopic laser refractive surgery in finite element model.

PURPOSE: A customized myopic refractive surgery was simulated by establishing a finite element model of the human eye, after which we studied the wave front aberrations induced by biomechanical effects and ablation profile after wave front-guided LASIK surgery. METHODS: Thirty myopia patients (i.e., 60 eyes) without other eye diseases were selected. Their ages, preoperative spherical equivalent, astigmatism, and wave front aberration were then obtained, in addition to the mean spherical equivalent error range - 4 to - 8D. Afterward, wave front-guided customized LASIK surgery was simulated by establishing a finite element eye model, followed by the analysis of the wave front aberrations induced by the surface displacement from corneal biomechanical effects, as well as customized ablation profile. Finally, the preoperative and induced aberrations were statistically analyzed. RESULTS: Comatic aberrations were the main wave front abnormality induced by biomechanical effects, and the wave front aberrations induced by the ablation profile mainly included coma and secondary coma, as well as sphere and secondary-sphere aberrations. Overall, the total high-order aberrations (tHOAs), total coma (C31), and sphere ([Formula: see text]) increased after wave front-guided customized LASIK surgery. According to our correlation analyses, coma, sphere, and tHOAs were significantly correlated with decentration. Additionally, the material parameters of ocular tissue were found to affect the postoperative wave front aberrations. When the material parameters of the sclera remained constant but those of cornea increased, the induced wave front aberrations were reduced. CONCLUSION: All biomechanical effects of cornea and ablation profile had significant effects on postoperative wave front aberrations after customized LASIK refractive surgery; however, the effects of the ablation profile were more notorious. Additionally, the characteristics of biomechanical materials have influence on the clinical correction effect.

Therapeutic Drug Monitoring of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation: A Pilot Single-Center Study in Taiwan.

(1) Background: Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; (2) Methods: Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC-MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; (3) Results: The LC-MS/MS method was validated with an analyte recovery of 88-99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; (4) Conclusions: This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future.

Biomechanical responses of the cornea after small incision lenticule extraction (SMILE) refractive surgery based on a finite element model of the human eye.

PURPOSE: To investigate the biomechanical responses of the human cornea after small incision lenticule extraction (SMILE) procedures, especially their effects of SMILE surgery on stress and strain. METHODS: Based on finite element analysis, a three-dimensional (3D) model of the human eye was established to simulate SMILE refractive surgery procedures. Stress and strain values were calculated by inputting the intraocular pressure (IOP). RESULTS: After SMILE refractive surgery procedures, the stress and strain of the anterior and posterior corneal surfaces were significantly increased. The equivalent stress and strain on the anterior and posterior corneal surfaces increased with increasing diopter and were concentrated in the central area, whereas the values of stress and strain at the incision site on the anterior surface of the cornea were approximately 0. Compared with the anterior corneal surface, the stress and strain of the posterior surface were larger. Increasing IOP caused an approximately linear change in stress and a nonlinear increase in corneal strain. In addition, we found that the incision sizes and direction had less of an influence on stress and strain. In summary, SMILE surgery increased the equivalent stress and strain on the human cornea. CONCLUSIONS: The equivalent stress and strain of the anterior and posterior human corneal surfaces increased after SMILE refractive surgery; these increases were particularly noticeable on the posterior surface of the cornea.

Simulated biomechanical effect of aspheric transition zone ablation profiles after conventional hyperopia refractive surgery.

We studied the effects of the aspheric transition zone on the optical wavefront aberrations, corneal surface displacement, and stress induced by the biomechanical properties of the cornea after conventional laser in situ keratomileusis (LASIK) refractive surgery. The findings in this study can help improve visual quality after refractive surgery. Hyperopia correction in 1-5D was simulated using five types of aspheric transition zones with finite element modeling. The algorithm for the simulations was designed according to the optical path difference. Wavefront aberrations were calculated from the displacements on the anterior and posterior corneal surfaces. The vertex displacements and stress on the corneal surface were also evaluated. The results showed that the aspheric transition zone has an effect on the postoperative visual quality. The main wavefront aberrations on the anterior corneal surface are defocus, y-primary astigmatism, x-coma, and spherical aberrations. The wavefront aberrations on the corneal posterior surface were relatively small and vertex displacements on the posterior corneal surface were not significantly affected by the aspheric transition zone. Stress analysis revealed that the stress on the cutting edge of the anterior corneal surface decreased with the number of aspheric transition zone increased, and profile #1 resulted in the maximum stress. The stress on the posterior surface of the cornea was more concentrated in the central region and was less than that on the anterior corneal surface overall. The results showed that the aspheric transition zone has an effect on postoperative aberrations, but wavefront aberrations cannot be eliminated. In addition, the aspheric transition zone influences the postoperative biomechanical properties of the cornea, which significantly affect the postoperative visual quality.

Eradication of T-ALL Cells by CD7-targeted Universal CAR-T Cells and Initial Test of Ruxolitinib-based CRS Management.

PURPOSE: Although chimeric antigen receptor T-cell (CAR-T) therapy development for B-cell malignancies has made significant progress in the last decade, broadening the success to treating T-cell acute lymphoblastic leukemia (T-ALL) has been limited. We conducted two clinical trials to verify the safety and efficacy of GC027, an "off-the-shelf" allogeneic CAR-T product targeting T-cell antigen, CD7. Here, we report 2 patients as case reports with relapsed/refractory T-ALL who were treated with GC027. PATIENTS AND METHODS: Both the trials reported here were open-label and single-arm. A single infusion of GC027 was given to each patient after preconditioning therapy. RESULT: Robust expansion of CAR-T cells along with rapid eradication of CD7+ T lymphoblasts were observed in the peripheral blood, bone marrow, and cerebrospinal fluid. Both patients achieved complete remission with no detectable minimal residual disease. At data cutoff, 30 September 2020, 1 of the 2 patients remains in ongoing remission for over 1 year after CAR T-cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in both patients and was managed by a novel approach with a ruxolitinib-based CRS management. Ruxolitinib showed promising activity in a preclinical study conducted at our center. No graft-versus-host disease was observed. CONCLUSIONS: The two case reports demonstrate that a standalone therapy with this novel CD7-targeted "off-the-shelf" allogeneic CAR-T therapy may provide deep and durable responses in select patients with relapsed/refractory T-ALL. GC027 might have a potential to be a promising new approach for treating refractory/relapsed T-ALL. Further studies are warranted.

Gut Microbiome Alterations Precede Cerebral Amyloidosis and Microglial Pathology in a Mouse Model of Alzheimer's Disease.

Emerging evidence suggests that the gut microbiome actively regulates cognitive functions and that gut microbiome imbalance is associated with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. However, the changes in gut microbiome composition in AD and their association with disease pathology, especially in the early stages, are unclear. Here, we compared the profiles of gut microbiota between APP/PS1 transgenic mice (an AD mouse model) and their wild-type littermates at different ages by amplicon-based sequencing of 16S ribosomal RNA genes. Microbiota composition started diverging between the APP/PS1 and wild-type mice at young ages (i.e., 1-3 months), before obvious amyloid deposition and plaque-localized microglial activation in the cerebral cortex in APP/PS1 mice. At later ages (i.e., 6 and 9 months), there were distinct changes in the abundance of inflammation-related bacterial taxa including Escherichia-Shigella, Desulfovibrio, Akkermansia, and Blautia in APP/PS1 mice. These findings suggest that gut microbiota alterations precede the development of key pathological features of AD, including amyloidosis and plaque-localized neuroinflammation. Thus, the investigation of gut microbiota might provide new avenues for developing diagnostic biomarkers and therapeutic targets for AD.

Comparison between single-agent and combination chemotherapy as second-line treatment for advanced non-small cell lung cancer: a multi-institutional retrospective analysis.

PURPOSE: Doublet combination chemotherapy is commonly considered a second-line treatment for advanced non-small cell lung cancer (NSCLC) in China. This multi-institutional retrospective analysis evaluated and compared the efficacy between combination and mono-therapy after platinum-based first-line chemotherapy in Chinese patients with advanced NSCLC. METHODS: We retrospectively reviewed 335 patients who received second-line chemotherapy for advanced NSCLC. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate (RR) and toxicity. Treatment-free interval (TFI) was used for further stratification analysis. The Cox proportional hazards model was used for multivariate analysis. RESULTS: Two hundred and fifty-three patients received doublet combination chemotherapy and 82 received single-agent chemotherapy. PFS was significantly prolonged in combination group compared to single-agent group (median 5.70 vs 3.70 months; HR 0.62; 95% CI 0.45-0.85; p < 0.001). The RR was significantly higher in the combination group than in the single-agent group (29.25% vs. 10.98%; p = 0.001). OS was also prolonged in combination group versus single-agent group (median 13.30 vs. 11.45 months, respectively; HR 0.70; 95% CI 0.52-0.95; p = 0.023). Among patients with TFI of ≥ 6 months, PFS and OS of the combination group were significantly increased than the single-agent group (median PFS, 6.67 vs. 3.80 months, p = 0.002; median OS, 13.60 vs. 11.45 months, p = 0.013). Grade III/IV toxicity was similar between the two groups (p = 0.113). Through multivariate analyses, we found that Eastern Cooperative Oncology Group (ECOG) score (p < 0.001), further-line treatment (p < 0.001) and combination chemotherapy (p = 0.024) were the independent prognostic factors. CONCLUSION: Compared with mono-therapy, combination chemotherapy was a better second-line option for Chinese patients with good performance status, especially in those with TFI of ≥ 6 months.

Theoretical Analysis of Wave-Front Aberrations Induced from Conventional Laser Refractive Surgery in a Biomechanical Finite Element Model.

Purpose: To examine the biomechanical effects-induced wave-front aberrations after conventional laser refractive surgery. Methods: A finite element model of the human eye was established to simulate conventional laser refractive surgery with corrected refraction from -1 to -15 diopters (D). The deformation of the anterior and posterior corneal surfaces was obtained under the intraocular pressure (IOP). Then, the surface displacement was converted to wave-front aberrations. Results: Following conventional refractive surgery, significant deformation of the anterior and posterior corneal surfaces occurred because of the corneal biomechanical effects, resulting in increased residual wave-front aberrations. Deformation of the anterior surface resulted in a hyperopic shift, which was significantly increased with the increasing refractive correction. The residual high-order aberrations consisted of spherical aberration, vertical coma, and y-trefoil. Spherical aberration was significantly positively correlated to enhanced refraction correction. The effect of posterior corneal surface on induced wave-front aberration was less than the anterior corneal surface. The IOP slightly affects the postoperative defocus, coma, and spherical aberration. When treatment decentration occurred during the procedure, the hyperopic shift decreased as the eccentricity increased. Treatment decentration had a significant impact on the spherical aberration and the coma. In addition, the ocular tissue elasticity played a key role in hyperopic shift, whereas it had little effect on the other aberrations. Conclusions: Among the many factors that affect high-order aberrations after conventional laser refractive surgery, the alterations in corneal morphology caused by biomechanical effects must be considered, as they can lead to an increase in postoperative residual wave-front aberrations.

Effects of the LASIK flap thickness on corneal biomechanical behavior: a finite element analysis.

BACKGROUND: It is well known that the biomechanical properties change after LASIK refractive surgery. One reason is the impact of flap creation on the residual stroma. The results have revealed that the change is closely related with the flap thickness in several studies. However, the quantitative relationships between the distributions of displacement and stress on the corneal surface and flap thickness have not been studied. The aim of the study was to quantify evaluate the biomechanical change caused by the LASIK flap. METHODS: By building a finite element model of the cornea, the displacement, the stress and the strain on the corneal surface were analyzed. RESULTS: The results showed that the corneal flap could obviously cause the deformation of the anterior corneal surface. For example, the displacement of the corneal vertex achieved 15 µm more than that without corneal flap, when the thickness of corneal flap was 120 µm thick. This displacement was enough to cause the change of aberrations in the human eyes. In the central part of the cornea, the stress on the anterior corneal surface increased with flap thickness. But the change in the stress on the posterior corneal surface was significantly less than that on the anterior surface. In addition, the stress in the central part of the anterior corneal surface increased significantly as the intra-ocular pressure (IOP) increase. Furthermore the increase of IOP had a clearly less effect on stress distribution at the edge of the cornea. Distributions of strain on the corneal surface were similar to those of stress. CONCLUSIONS: The changes in the biomechanical properties of cornea after refractive surgery should not be ignored.

Methylation­driven genes PMPCAP1, SOWAHC and ZNF454 as potential prognostic biomarkers in lung squamous cell carcinoma.

Of the different types of lung cancer, lung squamous cell cancer (LUSC) has the second highest rates of morbidity and mortality, which have been increasing in recent years. Epigenetic abnormalities may serve as potential biomarkers and diagnostic and/or therapeutic targets, which may help to monitor and improve the prognosis of patients with cancer. In the present study, data were obtained from The Cancer Genome Atlas database and survival and joint survival analyses were conducted using the R MethylMix package. Peptidase, mitochondrial processing a subunit pseudogene 1 (PMPCAP1), sosondowah ankyrin repeat domain family member C (SOWAHC) and zinc finger protein (ZNF) 454 were identified as independent prognosis­related hub methylation­driven genes (MDGs). Of these three genes, PMPCAP1 and SOWAHC, characterized by hypomethylation and high expression levels, were associated with poor prognosis in patients with LUSC, whilst ZNF454 was associated with an improved prognosis. In addition, pathway enrichment analysis suggested that PMPCAP1, SOWAHC and ZNF454 were primarily involved in gene expression or transcription pathways. Furthermore, 5, 1 and 10 key methylation sites of PMPCAP1, SOWAHC and ZNF454, respectively, were confirmed to be significantly relevant to gene expression, establishing a basis for further investigation into the mechanisms and more precise targets of these 3 genes. In conclusion, the MDGs PMPCAP1, SOWAHC and ZNF454 may be potential prognostic biomarkers of LUSC for guiding diagnosis and therapy options, as well as providing a theoretical basis for further investigation.

Identification of methylation-driven genes related to prognosis in clear-cell renal cell carcinoma.

With the participation of the existing treatment methods, the prognosis of advanced clear-cell renal cell carcinoma (ccRCC) is poor. More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation-driven genes in ccRCC. We analyzed the open data of ccRCC in The Cancer Genome Atlas database to obtain ccRCC-related methylation-driven genes, and then carried out pathway enrichment, survival, and joint survival analyses. More important, we deeply explored the correlation between differential methylation sites and the expression of these driving genes. Finally, we screened 29 methylation-driven genes via MethylMix, of which six were significantly associated with the survival of ccRCC patients. This study demonstrated that the effect of hypermethylation or hypomethylation on prognosis is different, and the level of methylation of key methylation sites is associated with gene expression. We identified methylation-driven genes independently predicting prognosis in ccRCC, which offers theoretical support in bioinformatics for the study of methylation in ccRCC and a new perspective for the epigenetic study of ccRCC.

Mediastinal Germ Cell Tumor-associated Histiocytic Proliferations Treated With Thalidomide Plus Chemotherapy Followed by Alemtuzumab-containing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report.

Mediastinal nonseminomatous germ cell tumor (MNSGCT)-associated histiocytic proliferations are rare and rapidly fatal disorders. Standard treatment modalities have yet to be established.We report a case of MNSGCT-associated hemophagocytic syndrome that evolved into malignant histiocytosis/disseminated histiocytic sarcoma (MH/HS), which was initially treated with intravenous immunoglobulin, corticosteroids, and cyclosporine. Then, thalidomide plus cyclophosphamide, adriamycin, oncovin, prednisolone chemotherapy followed by alemtuzumab-containing reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT) was used as salvage therapy.The severe constitutional symptoms and pancytopenia resolved shortly after thalidomide with cyclophosphamide, adriamycin, oncovin, prednisolone. After PBSCT, the patient developed steroid-dependent skin graft-versus-host disease, but maintained a functional life for 1.5 years. Rapid resolution of chronic graft-versus-host disease preceded the fulminant recurrence of hemophagocytic syndrome and MH/HS.Thalidomide plus chemotherapy followed by alemtuzumab-containing reduced intensity allogeneic PBSCT is effective in allaying MNSGCT-associated histiocytic disorders, but does not prevent eventual relapse. However, further posttransplant immune modulation should be developed to completely eradicate the residual MH/HS cells.

Idiopathic Pneumonia Syndrome and Thrombotic Microangiopathy Following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation and Posttransplant Cyclophosphamide: A Case Report.

Posttransplant high-dose cyclophosphamide (pT-HDCy) following T-cell-replete haploidentical bone marrow (BM) transplantation has been successfully utilized to control alloreactivity, mainly in ameliorating graft-versus-host disease (GVHD) and graft rejection. Recently, peripheral blood stem cells (PBSCs) have also been suggested to be a feasible and effective graft alternative to BM in the same setting. We report a case with refractory Hodgkin lymphoma treated with haploidentical PBSC transplantation with nonmyeloablative conditioning and pT-HDCy. Although engraftment with complete donor chimerism was achieved without classical GVHD, the patient suffered from idiopathic pneumonia syndrome followed by thrombotic microangiopathy. Although idiopathic pneumonia syndrome and thrombotic microangiopathy improved after treatment, the patient's lymphoma rapidly progressed nonetheless. This outcome may suggest that the alloreactivity against the classical GVHD targets is successfully eradicated by pT-HDCy, but alloreactivity against the lungs and endothelial cells is differentially preserved when utilizing granulocyte colony-stimulating factor-mobilized PBSCs as the graft source. The graft-versus-Hodgkin lymphoma effect was not observed in our patient.

Superoxide dismutase of Streptococcus suis serotype 2 plays a role in anti-autophagic response by scavenging reactive oxygen species in infected macrophages.

Streptococcus suis serotype 2 (SS2) causes septic shock and meningitis. However, its pathogenesis is still not well-understood. We have recently shown that superoxide dismutase sodA of SS2 is a virulence factor probably by increasing resistance to oxidative stresses. Reactive oxygen species (ROS) are products of the respiratory burst of phagocytic cells and have been shown to activate autophagy. We wanted to know if and how SS2 explores its sodA to interfere with cell autophagic responses. A sodA deletion mutant (Δsod) was compared with its parent and complemented strain in autophagic response in the murine macrophage cell line RAW264.7. We found that the Δsod mutant induced significant autophagic responses in infected cells, shown as increased LC3 lipidation (LC3-II) and EGFP-LC3 punctae, than those infected by its parent or complemented strain at 1 or 2h post-infection. Co-localization of the autophagosomal EGFP-LC3 vesicles with lysosomes was seen in cells infected with Δsod mutant and its parent strain, indicating that SS2 infection induced complete autophagic responses. Reduced autophagic responses of cells infected with the wild-type strain might be related to decreased ROS by the scavenging effect of its sodA, as shown by increased superoxide anion or ROS level in cells infected with the Δsod mutant and in the cell free xanthine oxidase-hypoxanthine ROS-generating system, as compared with its parent or complemented strain. Taken together, SS2 makes use of its sodA for survival not only by scavenging ROS but also by alleviating the host autophagic responses due to ROS stimulation.

Long-term cancer-free survival after infusion of autologous cord blood cells for rejection-unrelated cord blood graft after myeloablative conditioning for t-MDS: a case report.

Autologous cord blood transplantations are rarely applied in patients with hematologic as well as metastatic solid cancers since contamination of malignant clones is a concern. We report a case of therapy-related myelodysplasia after metastatic neuroblastoma who suffered from graft rejection and life-threatening infections after a myeloablative unrelated cord blood transplantation. The patient experiences long-term survival, free from leukemia/neuroblastoma after infusion of autologous cord blood cells. It suggests that autologous cord blood transplantation after high dose therapy might be a curative strategy for certain hematologic or metastatic solid cancers.