Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Multiple Functional Bonds Integrated Interphases for Long Cycle Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have garnered significant interest as one of the most promising energy suppliers for power grid energy storage. However, the poor electrode/electrolyte interfacial stability leads to continual electrolyte decomposition and transition metal dissolution, resulting in rapid performance degradation of SIBs. In this work, we propose a strategy integrating multiple functional bonds to regulate electrode/electrolyte interphase by triple-coupling of succinonitrile (SN), sodium hexafluorophosphate (NaPF6) and fluorinated ethylene carbonate (FEC). Theoretical calculation and experiment results show that the solvation structure of Na+ and ClO4- is effectively reconfigured by the solvated FEC, SN and PF6- in PC-based carbonate electrolyte. The newly developed electrolyte demonstrates increased Na+-FEC coordination, weakened interaction of Na+-PC and participation of SN and PF6- anions in solvation, resulting in the formation of a conformal interfacial layer comprising of sodium oxynitrides (NaNxOy), sodium fluoride (NaF) and phosphorus oxide compounds (NaPxOy). Consequently, a 3 Ah pouch full cell of hard carbon//NaNi1/3Fe1/3Mn1/3O2 exhibits an excellent capacity retention of 90.4% after 1000 cycles. Detailed postmortem analysis of interface chemistry is further illustrated by multiple characterization methods. This study provides a new avenue for developing electrolyte formulations with multiple functional bonds integrated interphases to significantly improve the long-term cycling stability of SIBs.

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%). METHODS: Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. RESULTS: Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. CONCLUSIONS: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell-engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. PLAIN LANGUAGE SUMMARY: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

Global, regional, and national burden of kidney dysfunction from 1990 to 2019: a systematic analysis from the global burden of disease study 2019.

OBJECTIVE: We aim to explore the prevalence and temporal trends of the burden of kidney dysfunction (KD) in global, regional and national level, since a lack of related studies. DESIGN: Cross-sectional study. MATERIALS: The data of this research was obtained from Global Burden of Diseases Study 2019. The estimation of the prevalence, which was measured by the summary exposure value (SEV), and attributable burden of KD was performed by DisMod-MR 2.1, a Bayesian meta-regression tool. The Spearman rank order correlation method was adopted to perform correlation analysis. The temporal trends were represented by the estimated annual percentage change (EAPC). RESULTS: In 2019, there were total 3.16 million deaths and 76.5 million disability-adjusted life years (DALYs) attributable to KD, increased by 101.1% and 81.7% compared with that in 1990, respectively. From 1990 to 2019, the prevalence of KD has increased in worldwide, but decreased in High-income Asia Pacific. Nearly 48.5% of countries globally, such as South Africa, Egypt and Mexico had increased mortality rates of KD from 1990 to 2019 while 44.6% for disability rate. Countries with lower socio-demographic index (SDI) are facing a higher prevalence as well as mortality and disability rate compared with those with higher SDI. Compared with females, the prevalence of KD was lower in males, however the attributable mortality and disability rate were higher in all years from 1990 to 2019. CONCLUSION: With the progress of senescent, we will face more severe challenges of reducing the prevalence and attributable burden of KD, especially in regions with lower SDI. Effective measures are urgently required to alleviate the prevalence and burden of KD.

Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia.

Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival. Mechanistically, we reveal that PRMT1 methylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells. We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973 methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.

Axial Ligand Coordination Tuning of the Electrocatalytic Activity of Iron Porphyrin Electrografted onto Carbon Nanotubes for the Oxygen Reduction Reaction.

The oxygen reduction reaction (ORR) is essential in many life processes and energy conversion systems. It is desirable to design transition metal molecular catalysts inspired by enzymatic oxygen activation/reduction processes as an alternative to noble-metal-Pt-based ORR electrocatalysts, especially in view point of fuel cell commercialization. We have fabricated bio-inspired molecular catalysts electrografted onto multiwalled carbon nanotubes (MWCNTs) in which 5,10,15,20-tetra(pentafluorophenyl) iron porphyrin (iron porphyrin FeF20 TPP) is coordinated with covalently electrografted axial ligands varying from thiophene to imidazole on the MWCNTs' surface. The catalysts' electrocatalytic activity varied with the axial coordination environment (i. e., S-thiophene, N-imidazole, and O-carboxylate); the imidazole-coordinated catalyst MWCNTs-Im-FeF20 TPP exhibited the highest ORR activity among the prepared catalysts. When MWCNT-Im-FeF20 TPP was loaded onto the cathode of a zinc-air battery, an open-cell voltage (OCV) of 1.35 V and a maximum power density (Pmax ) of 110 mW cm-2 were achieved; this was higher than those of MWCNTs-Thi-FeF20 TPP (OCV=1.30 V, Pmax =100 mW cm-2 ) and MWCNTs-Ox-FeF20 TPP (OCV=1.28 V, Pmax =86 mW cm-2 ) and comparable with a commercial Pt/C catalyst (OCV=1.45 V, Pmax =120 mW cm-2 ) under similar experimental conditions. This study provides a time-saving method to prepare covalently immobilized molecular electrocatalysts on carbon-based materials with structure-performance correlation that is also applicable to the design of other electrografted catalysts for energy conversion.

Current Management and New Developments in the Treatment of ALL.

With the recent advent of newer targeted therapies, including blinatumomab, inotuzumab ozogamicin, tyrosine kinase inhibitors (TKIs), and CAR T cells, treatment approaches to newly diagnosed as well as relapsed/refractory acute lymphoblastic leukemia (ALL) have changed. This chapter summarizes the newest treatment approaches in newly diagnosed T-cell and B-cell ALL, as well as the use of novel therapies for relapsed and refractory ALL.

Reactivation of human herpesvirus 6 in pediatric allogeneic hematopoietic stem cell transplant recipients.

BACKGROUND: Reactivation of human herpesvirus 6 (HHV-6) occurs in 30%-50% of patients (pts) who receive allogeneic (allo) hematopoietic stem cell transplant (HCT). However, the recommendation for post-transplant HHV-6 monitoring and treatment in pediatric pts is not well established. METHODS: HHV-6 incidence rates and the clinical outcomes were reported for 139 pediatric pts (≤18 years) undergoing first allo-HCT at City of Hope from July 2011 to July 2017, for whom HHV-6 was monitored weekly throughout HCT hospitalization. For 57 pediatric pts, who underwent first HCT from January 2009 to July 2011, HHV-6 was tested as clinically indicated and only rates of HHV-6 viremia were collected. RESULTS: From July 2011 to July 2017, HHV-6 was detected in 88/139 pts (63%). The frequency of HHV-6 viremia was associated with malignant diagnoses, myeloablative conditioning, and cord blood HCT. Treatment with antiviral agents was offered to symptomatic pts with a higher viral load (VL), for whom the time to VL clearance was longer and the frequency of subsequent recurrences was higher. Pts with a lower VL cleared HHV-6 without treatment. HHV-6 viremia was associated with a higher frequency of grade II-IV acute graft-versus-host disease (GVHD) (P = .022), but did not affect overall survival (OS), disease-free survival (DFS), non-relapsed mortality (NRM), myeloid, or platelet (Plt) engraftment. CONCLUSIONS: HHV-6 weekly screening is not necessary for all HCT pts but may be considered for high-risk pts with malignant diagnoses undergoing cord blood HCT; otherwise, HHV-6 should be tested as clinically indicated. Only symptomatic pts (especially with a high VL > 25 000) could benefit from treatment. HHV-6 viremia at the time of initiation and administration of the conditioning regimen cleared promptly without the need to augment the transplant process.

Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

Safety of Isavuconazonium Sulfate in Pediatrics Patients With Hematologic Malignancies and Hematopoietic Cell Transplantation With Invasive Fungal Infections: A Real World Experience.

PURPOSE: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population. PATIENTS AND METHODS: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages. RESULTS: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA. CONCLUSIONS: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Research on the Application Value of Serum and Urine ß2-Microglobulin in Immunoglobulin a Nephropathy.

BACKGROUND: To compare the application value of serum and urinary ß2-microglobulin in immunoglobulin A nephropathy (IgAN). METHODS: Two hundred thirteen patients were hospitalized at the First Affiliated Hospital of Bengbu Medical College in China because of physical abnormalities and diagnosed with IgAN by means of renal biopsy between January 2010 and December 2018. ß2-MG levels in serum and urine were detected through immunoturbidimetric methods. The renal histopathology was quantified according to Katafuchi semi-quantitative standards and Lee's grading. RESULTS: One hundred twenty-four patients were male and 89 cases were female, for a 1.39:1 male to female ratio. The average age was 38.25 ± 12.48 years old when patients received their first renal biopsy. The levels of serum ß2-MG and urine ß2-MG increased gradually with the aggravation of tubulointerstitial lesions. Results of correlation analysis showed that serum ß2-MG had higher application value. Serum ß2-MG levels were positively correlated with SCr and tubulointerstitial lesions (r = 0.840, 0.652, p = 0.000), negatively correlated with CG-eGFR (r = -0.680, p = 0.000). The results of multivariate logistic regression analysis showed that serum ß2-MG was a marker of independent risk factor for the score of tubulointerstitial lesions ≥ 3 (OR = 6.649, p = 0.000). ROC analysis showed better diagnostic performance for serum ß2-MG, with the optimal cutoffs in predicting tubulointerstitial score ≥ 1, score ≥ 4 and score ≥ 7 of 1.905 mg/L, 2.13 mg/L, and 4.49 mg/L, respectively. CONCLUSIONS: Serum ß2-MG is valuable in evaluating renal function and pathological lesions in IgAN patients and has significant predictive value in evaluating tubulointerstitial lesions. Serum ß2-MG may be used as a non-invasive diagnostic indicator for predicting renal function and tubulointerstitial lesions in IgAN.

A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies.

Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Results: Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Conclusions: Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses.

Unexpected mechanism of colitis amelioration by artesunate, a natural product from Artemisia annua L.

BACKGROUND: Artemisinin and its derivatives are known to exert immunosuppressive effects through modulating adaptive immunity. We investigated a novel role of artesunate in regulating innate immunity, including both macrophages (MΦ) and dendritic cells (DCs), which are known to involve in DSS-induced colitis. METHODS: Effects of artesunate on innate immunity were extensively evaluated, both in vivo using DSS-colitis model with WT and T cell-deficient RAG mice (RAG-/-) and in vitro using cell culture models, including in-depth analyses of MΦ/DC apoptosis and cytokine expression by flow cytometry, Western blot, or immunohistology. RESULTS: Unexpectedly, artesunate significantly ameliorated the DSS colitis of both WT and RAG1-/- mice with similar potency, suggesting a mechanism that involves primarily innate rather than adaptive immunity. In vivo mechanistic studies revealed that artesunate markedly induced apoptosis of lamina propria MΦs and DCs and suppressed mucosal TNF-α and IL-12p70 in DSS-colitis. In vitro, artesunate potently induced a dose- and time-dependent apoptosis of murine bone marrow-derived DCs and human THP-1 MΦs, through the caspases-9-mediated intrinsic pathway. Artesunate significantly decreased the secretion of IL-12p40/70 by DCs and TNF-α by MΦs. Furthermore, a combination of artesunate with an immunomodulator (methotrexate/triptolide/azathioprine) exhibited superior potency in promoting apoptosis of MΦs than any individual drug alone. CONCLUSIONS: The immunomodulatory mechanism of artesunate in colitis involves a novel and potent induction of the intrinsic apoptosis pathway of proliferating MΦs and DCs and suppression of IL-12 and TNF-α. Artemisinin and its derivatives are promising new therapeutic alternatives for IBD, either alone or in combination with other immunomodulators.

PUM2 Promotes Glioblastoma Cell Proliferation and Migration via Repressing BTG1 Expression.

PUM2, an RNA binding protein, is known to promote stem cell proliferation via repressing expressions of cell cycle genes. Similar with stem cells, malignant cells are characterized by unlimited proliferation and remote migration. However, roles of PUM2 in cancer development are controversial. Here, we investigated PUM2's role in glioblastoma development and its relationship with the cell cycle regulator BTG1. Immunoblotting and RT-qPCR were used to evaluate protein expression level and transcript level, respectively. ShRNAs were designed to knock down PUM2 and BTG1 expression. CCK-8 assay was used to evaluate cell viability. Cell migration assay and evasion assay were used to evaluate metastatic capability of glioblastoma cell. RNA pull-down assay and RNA immunoprecipitation assay were used to test the interaction between PUM2 and BTG1 3'UTR. PUM2 expression is elevated in glioblastoma tumor tissues as well as glioblastoma cell lines. PUM2 knockdown remarkably suppresses glioblastoma cell proliferation and migration. In addition, PUM2 knockdown increases BTG1 expression. RNA pull-down assay and RNA immunoprecipitation assay show PUM2 binds to BTG1 3'UTR directly. Furthermore, knockdown of BTG1 reverses the effect of PUM2 knockdown on glioblastoma cell proliferation and migration. Our results suggest that PUM2 promote glioblastoma development via repressing BTG1 expression.Key words: PUM2, BTG1, glioblastoma, cell proliferation, metastasis.

Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia.

Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425.

Use of Advanced Modalities Does Not Guarantee Early Detection of Small-Bowel Crohn's Disease in the Absence of Complications.

BACKGROUND This study investigated the approach for detection of small-bowel (SB) Crohn's disease (CD) in the absence of complications at diagnosis using advanced modalities. MATERIAL AND METHODS Patients diagnosed with CD in Renji Hospital from 2005 to 2014 were divided into 2 groups by year of diagnosis: 2005 to 2009 and 2010 to 2014. The modalities used and the clinical characteristics of patients were retrospectively examined. RESULTS Advanced modalities did not detect higher rate of non-stricturing/non-penetrating disease in 2010 to 2014 than older modalities in 2005 to 2009. Further analysis showed that a stricturing complication was significantly more common in patients with SB CD than in those who had CD with SB and colonic involvement, and the duration from symptom onset to lesion detection was significantly longer in patients with SB CD than in those who had CD with SB and colonic involvement. Fewer patients with SB CD underwent SB capsule endoscopy compared to the other advanced modalities. Abdominal pain (74.4%) was the most common presentation, and 94.0% patients with SB CD presented gastrointestinal bleeding and anemia. CONCLUSIONS Early detection of SB CD without complications remains difficult even if advanced modalities are introduced. Our hypothesis is that the fecal occult blood test and routine blood test should be administered to patients with abdominal pain or gastrointestinal manifestations. Once the patients are found to have GI bleeding or anemia, they would be further examined according to the guideline and SBCE would be used in the early stage of SB CD.

HLA Haploidentical Stem Cell Transplant with Pretransplant Immunosuppression for Patients with Sickle Cell Disease.

Allogeneic stem cell transplantation (HCT) is curative in patients with severe sickle cell disease (SCD), but a significant number of patients lack an HLA-identical sibling or matched unrelated donor. Mismatched related (haploidentical) HCT with post-transplant cyclophosphamide (PTCY) allows expansion of the donor pool but is complicated by high rates of graft failure. In this report we describe a favorable haploidentical HCT approach in a limited cohort of SCD patients with significant comorbidities. To reduce the risk of graft failure we administered the conditioning regimen of rabbit antithymocyte globulin, busulfan, and fludarabine preceded with 2 courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine and dexamethasone. Graft-versus-host disease (GVHD) prophylaxis consisted of PTCY on days +3 and +4 followed by tacrolimus and mycophenolate mofetil starting on day +5. Four patients (ages 13, 19, 19, and 23 years) received T cell-replete haploidentical stem cell infusion. All patients engrafted with 99.9% to 100% donor chimerism, and all patients continued with stable engraftment at the last follow-up (5 to 11 months post-transplant). Time to neutrophil engraftment was 14 to 26 days. Two patients had high levels of donor-specific anti-HLA antibodies, which required the implementation of an antibody management protocol. This facilitated neutrophil engraftment on day +16 and day +26, respectively. One patient developed grade I acute GVHD, which resolved. Three patients developed mild, limited skin GVHD that responded to conventional immunosuppressive therapy. Human herpesvirus-6 viremia was detected in 3 patients but resolved without treatment. One patient developed asymptomatic cytomegalovirus viremia that responded appropriately to standard therapy with ganciclovir. The prompt, stable engraftment and low toxicity in the post-transplant period makes PTIS with haploidentical transplant a promising option for patients with SCD.

Mink (Mustela vison) Gut Microbial Communities from Northeast China and Its Internal Relationship with Gender and Food Additives.

It is well documented that the microbial interactions and biodiversity play an important role in health and disease in mammalian species. There is a rare study about gut microbiota of Mustelidae family. In this study, 40 male and female minks from Northeast China were divided into three groups and fed until they reached maturity. The V3 region of 16S rRNA genes was amplified and sequenced using NGS. There were 526 OTUs principally concentrated among five bacterial phyla. Two points about mink's body weight gaining were observed: (1) the weight of male individuals increased more rapidly than female individuals; (2) the weight of individuals whose feed was supplemented with Chinese herb additives increased more rapidly than individuals without giving food additives. The differences of microorganism abundance were shown in two points: (1) two genera which had ≥2-fold change difference were found between male and female minks. (2) Ten genera which had a ≥2-fold change difference were found among minks with and without Chinese herb additive. Findings from this study provide new and fundamental knowledge on the gut microbiota composition of minks farmed in Northeast China, which can contribute to the general well-being of minks worldwide.

Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia.

New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure.