Cu-Catalyzed Asymmetric Dicarboxylation of 1,3-Dienes with CO2.

Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO2 represents a straightforward and sustainable route to dicarboxylic acids, it is still highly challenging and limited to generation of achiral or racemic dicarboxylic acids. To date, catalytic asymmetric dicarboxylation with CO2 to give chiral dicarboxylic acids has not been reported. Herein, we report the first asymmetric dicarboxylation of 1,3-dienes with CO2 via Cu catalysis. This strategy provides an efficient and environmentally benign route to chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The copper self-relay catalysis, that is, Cu-catalyzed boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give dicarboxylates, is key to the success of this dicarboxylation. Moreover, this protocol exhibits broad substrate scope, good functional group tolerance, easy product derivatizations, and facile synthesis of chiral liquid crystalline polyester and drug-like scaffolds.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study.

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: VZV reactivation following antiviral prophylaxis discontinuation.

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8+ cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT.

Universal occurrence of organophosphate tri-esters and di-esters in marine sediments: Evidence from the Okinawa Trough in the East China Sea.

Despite numerous data on organophosphate tri-esters (tri-OPEs) in the environment, literatures on organophosphate di-esters (di-OPEs) in field environment, especially marine sediments remain scarce. This study addresses this gap by analyzing 35 abyssal sediment samples from the middle Okinawa Trough in the East China Sea. A total of 25 tri-OPEs and 10 di-OPEs were determined, but 13 tri-OPEs and 2 di-OPEs were nondetectable in any of these sediment samples. The concentrations of ∑12tri-OPE and ∑8di-OPE were 0.108-32.2 ng/g (median 1.11 ng/g) and 0.548-15.0 ng/g (median 2.74 ng/g). Chlorinated (Cl) tri-OPEs were the dominant tri-esters, accounting for 47.5 % of total tri-OPEs on average, whereas chlorinated di-OPEs represented only 19.2 % of total di-OPEs. This discrepancy between the relatively higher percentage of Cl-tri-OPEs and lower abundance of Cl-di-OPEs may be ascribed to the stronger environmental persistence of chlorinated tri-OPEs. Source assessment suggested that di-OPEs were primarily originated from the degradation of tri-OPEs rather than industrial production. Long range waterborne transport facilitated by oceanic currents was an important input pathway for OPEs in sediments from the Okinawa Trough. These findings enhance the understanding of the sources and transport of OPEs in marine sediments, particularly in the Okinawa Trough.

Three new phenylpropanoid glucosides and a new tyramine-type alkamide from Piper puberulum.

Three new phenylpropanoid glycosides, piperpubelide (1), 1-propionyl-3-hydroxy-phenyl-4-O-ß-D-glucopyranoside (2), and 1-propionyl-4-hydroxy-phenyl-3-O-ß-D-glucopyranoside (3), a new tyramine-type alkamide, puberulumine L (4), together with thirteen known compounds (5-17) were isolated from Piper puberulum (Benth.) Maxim. Their structures were elucidated by analysis of spectroscopic data involving NMR, IR, UV, and HRESIMS data. Calculated and experimental ECD was used to confirm the configuration of compound 1. Compounds 14, 16, and 17 exhibited relatively positive DPPH radical scavenging activities, with corresponding EC50 of 10.23, 24.12, and 21.83 µM, respectively. In addition, compound 5 inhibited LPS-induced NO production in BV-2 microglia with an IC50 value of 18.05 µM.

Oral health self-management barriers among rural older adults in Guangxi, China: A qualitative study.

BACKGROUND: Objective: To understand the barriers associated with self-management of oral health among rural older adults in Guangxi, and to explore the high incidence of oral problems. This information will assist in the formulation of relevant strategies to solve the oral health problems in this population. METHODS: Taking a phenomenological approach, the current status of, and barriers to, oral health self-management in rural older adults from different regions of Guangxi were explored. Participants were purposively selected and interviewed face-to-face. RESULTS: The interviews yielded four overarching themes and six corresponding sub-themes pertaining to barriers in oral health self-management. These included: (1) Older adults' understanding of oral health and disease, perceptions of oral health and their oral health behaviours; (2) Problems in accessing oral health information; (3) Role of family support; and (4) Barriers to healthcare that included access to dental services, oral treatment experience and financial burden of access to dental care. CONCLUSION: Rural older adults in Guangxi face oral health self-management barriers. Improving access to oral healthcare services and changing existing oral health perceptions and habits may assist them in overcoming self-management challenges.

Synthesis of 2-benzyl N-substituted anilines via imine condensation-isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines.

A catalyst- and additive-free synthesis of 2-benzyl N-substituted anilines from (E)-2-arylidene-3-cyclohexenones and primary amines has been reported. The reaction proceeds smoothly through a sequential imine condensation-isoaromatization pathway, affording a series of synthetically useful aniline derivatives in acceptable to high yields. Mild reaction conditions, no requirement of metal catalysts, operational simplicity and the potential for scale-up production are some of the highlighted advantages of this transformation.

The nuclear factor erythroid 2-related factor 2 agonist tert-butylhydroquinone improves bone marrow mesenchymal stromal cell function in prolonged isolated thrombocytopenia after allogeneic haematopoietic stem cell transplantation.

Prolonged isolated thrombocytopenia (PT) is a life-threatening comorbidity associated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Our previous study indicated that dysfunctional bone marrow mesenchymal stromal cells (BM MSCs) played a role in PT pathogenesis and that reactive oxygen species (ROS) accumulation was related to BM MSC senescence and apoptosis. However, the mechanism of the increase in ROS levels in the BM MSCs of PT patients is unknown. In the current case-control study, we investigated whether nuclear factor erythroid 2-related factor 2 (NRF2), which is a central regulator of the cellular anti-oxidant response that can clear ROS in human BM MSCs, was associated with PT after allo-HSCT. We evaluated whether an NRF2 agonist (tert-butylhydroquinone, TBHQ) could enhance BM MSCs from PT patients in vitro. We found that BM MSCs from PT patients exhibited increased ROS levels and reduced NRF2 expression. Multivariate analysis showed that low NRF2 expression was an independent risk factor for primary PT [p = 0.032, Odds ratio (OR) 0.868, 95% confidence interval (CI) 0.764-0.988]. In-vitro treatment with TBHQ improved the quantity and function of BM MSCs from PT patients by downregulating ROS levels and rescued the impaired BM MSC support of megakaryocytopoiesis. In conclusion, these results suggested that NRF2 downregulation in human BM MSCs might be involved in the pathogenesis of PT after allo-HSCT and that BM MSC impairment could be improved by NRF2 agonist in vitro. Although further validation is needed, our data indicate that NRF2 agonists might be a potential therapeutic approach for PT patients after allo-HSCT.

Outcomes of haploidentical haematopoietic stem cell transplantation for adolescent and young adults with acute myeloid leukaemia.

We aimed to identify the efficacy of haploidentical related donor (HID) haematopoietic stem cell transplantation (HSCT) in adolescent and young adults (AYAs) with acute myeloid leukaemia (AML) in a large cohort. Consecutive AML AYAs (15-39 years old, n = 599) receiving HID HSCT in complete remission (CR) were included. The 3-year cumulative incidence of measurable residual disease occurrence, relapse and non-relapse mortality after HID HSCT was 28.6% (95% CI: 25.0-32.2), 11.6% (95% CI: 9.0-14.2) and 6.7% (95% CI: 4.7-8.7) respectively. The 3-year probability of event-free survival, leukaemia-free survival (LFS) and overall survival (OS) after HID HSCT was 60.7% (95% CI: 56.9-64.8), 81.7% (95% CI: 78.7-84.9) and 85.6% (95% CI: 82.8-88.4) respectively. In multivariable analysis, AML risk category at diagnosis and comorbidity burdens before HID HSCT were independently associated with LFS and OS. Compared to the older adults (≥ 40 years, n = 355) with AML receiving HID HSCT in CR during the same time period, AYAs have a lower incidence of non-relapse mortality and higher probabilities of LFS and OS. Thus, we firstly confirmed the safety and efficacy of HID HSCT in AYAs with AML-CR.

Predicting short-term and long-term mortalities from sepsis in patients who receive allogeneic haematopoietic stem cell transplantation.

Patients who receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) may develop sepsis, which result in a highly intensive care unit admission rate and mortality. Therefore, short-term and long-term prognostic models for sepsis after allo-HSCT are urgently needed. We enrolled patients receiving allo-HSCT who developed sepsis after allo-HSCT at Peking University People's Hospital between 2012 and 2021, including 287 patients who received allo-HSCT in 2018-2021 in the derivation cohort, and 337 patients in 2012-2017 in the validation cohort. Multivariate logistic regression analysis was used to identify prognostic factors, and these identified factors were incorporated into two scoring models. Seven independent factors (acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), total bilirubin, lactate dehydrogenase (LDH) and organ dysfunction [renal, lung and heart]) were included in the 6-month prognostic model, and six factors (cGVHD, C-reactive protein, LDH, organ dysfunction [lung, neurologic and coagulation]) were included in the 14-day prognostic model. The area under the receiver operating characteristic curves, calibration plots and decision curve analysis demonstrated the robust predictive performance of the models, better than the Sequential Organ Failure Assessment score. Early identification of patients with high risk of 6-month and 14-day death may allow clinicians to provide timely treatments and improve the therapeutic effects.

Isolation of three MiDi19-4 genes from mango, the ectopic expression of which confers early flowering and enhances stress tolerance in transgenic Arabidopsis.

MAIN CONCLUSION: Three Di19-4 genes were identified in mango. Overexpression of MiDi19-4B in A. thaliana promoted earlier flowering and enhanced drought, salt, and ABA resistance. Drought-induced protein 19 (Di19) is a drought-induced protein that is mainly involved in multiple stress responses. Here, three Di19-4 genes (MiDi19-4A/B/C) in mango (Mangifera indica L.) were identified, and the coding sequences (CDS) had lengths of 684, 666, and 672 bp and encoded proteins with 228, 222, and 224 amino acids, respectively. The promoters of the MiDi19-4 genes contained phytohormone-, light-, and abiotic stress-responsive elements. The MiDi19-4 genes were expressed in every tissue and highly expressed in leaves. Moreover, MiDi19-4 genes were highly correlated with the vegetative growth period and induced by polyethylene glycol (PEG) or salt stress. MiDi19-4B displayed the highest expression during the vegetative growth period and then showed decreased expression, and MiDi19-4B was highly expressed at both the late stage of the vegetative growth period and the initial stage of the flowering induction period. The 35S::GFP-MiDi19-4B fusion protein was located in the cell nucleus. The transgenic plants ectopically expressing MiDi19-4B exhibited earlier flowering and increased expression patterns of FRUITFULL (AtFUL), APETALA1 (AtAP1), and FLOWERING LOCUS T (AtFT). The drought and salt tolerance of MiDi19-4B transgenic plants was significantly increased, and these plants showed decreased sensitivity to abscisic acid (ABA) and considerably increased expression levels of drought- and salt-related genes and ABA signalling pathway genes. Additionally, bimolecular fluorescence complementation (BiFC) experiments revealed that the MiDi19-4B protein interacted with CAULIFLOWER (MiCAL1), MiCAL2, MiAP1-1, and MiAP1-2. Taken together, these results highlighted the important regulatory roles of MiDi19-4B in tolerance to multiple abiotic stresses and in flowering.

Prognostic factors for patients with hematologic malignancies admitted to the intensive care unit: is allogeneic transplantation still a risk factor?

The rate of intensive care unit (ICU) mortality in patients with hematologic malignancies is high. The risk factors for this were inconsistent across several previous studies, and there is currently no accepted consensus around risk factors for these patients. We aimed to identify which prognostic factors were associated with ICU mortality in critically ill patients with hematologic malignancies, nearly half of which were allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. In addition, we aimed to compare the characteristics and clinical outcomes of patients with and without allogenic allo-HSCT. In total, 217 patients with hematologic malignancies were enrolled consecutive, 119 (54.8%) of whom underwent HSCT (allo-HSCT: n = 115). All survivors were followed up with until August 1, 2022. The rate of ICU mortality in this cohort was 54.4%: 55.5 and 53.1% for the patients with and without HSCT, respectively (p = 0.724). The probabilities of survival after ICU admission were also comparable between the patients who had allo-HSCT and those who did not. A multivariable analysis revealed that cerebrovascular disease, hyperlactic acidemia on the day of ICU admission, lower platelet count, use of vasoactive drugs, and absence of noninvasive ventilation on the day of ICU admission were independent risk factors for ICU mortality. For patients with three to five of these risk factors, the rate of ICU mortality was as high as 84.6%, which was significantly higher than that of other patients. In this study, the ICU mortality rate in patients with hematologic malignancies was still high, particularly for those with multiple risk factors. However, allo-HSCT was not found to be a risk factor for ICU mortality.

Age-related SUMOylation of PLK1 is essential to meiosis progression in mouse oocytes.

Polo like kinase 1 (PLK1) is a protein kinase involved in regulating the spindle assembly and cell cycle control in mammalian oocytes. SUMOylation, one way of post-translational modification, regulates oocyte meiosis by controlling several substrates. However, the relation between PLK1 and SUMOylation in oocytes is still unknown. In this study, we investigated that whether PLK1 was modified by SUMOylation in oocytes and its potential relationship with age-related meiotic abnormalities. We showed that PLK1 had colocalization and protein interaction with Small Ubiquitin-Like Modifier (SUMO)-1 and SUMO-2/3 in mouse oocytes, indicating that PLK1 could be modified by SUMO-1 and SUMO-2/3. Overexpression of PLK1 SUMOylation site mutants PLK1K178R and PLK1K191R caused the increase of the abnormal spindle rate of oocytes and the decline of the first polar body extrusion rate with the abnormal localization of PLK1, suggesting that the SUMOylation modification of PLK1 is essential for normal meiosis in oocytes. Compared with young mice, the expression of PLK1 protein increased and the expression of SUMO-1 and SUMO-2/3 protein decreased in the oocytes of aged mice, indicating that the SUMOylation of PLK1 might be related to the mouse aging. Therefore, our data suggested that PLK1 could be SUMOylated by SUMO-1 and SUMO-2/3 in mouse oocytes and SUMOylation of PLK1 regulated the meiosis progression of oocytes which was related with aging.

Development and validation of a mortality predicting scoring system for severe aplastic anaemia patients receiving haploidentical allogeneic transplantation.

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

CMV infection combined with acute GVHD associated with poor CD8+ T-cell immune reconstitution and poor prognosis post-HLA-matched allo-HSCT.

Cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGVHD) are two major complications that contribute to a poor prognosis after hematopoietic stem cell transplantation (HSCT). Superior early immune reconstitution (IR) is associated with improved survival after HSCT. However, when all three factors, CMV infection, aGVHD, and IR, are concomitantly considered, the effects of the triple events on HSCT are still unknown and should be studied further. Thus we enrolled 185 patients who were diagnosed as hematological malignancies and treated with HLA-matched sibling transplantation (MST) between January 2010 and December 2014, of whom 83 were positive for CMV infection and 82 had aGVHD. Results showed that patients with both aGVHD and CMV infection had significantly higher non-relapse mortality (NRM), lower overall survival (OS), and delayed CD8+ T-cell IR. Multivariate analyses showed that both aGVHD combined with CMV infection and delayed CD8+ T-cell IR were independent risk factors for prognosis post-MST. Recurrent CMV infections are associated with poor CD8+ T-cell reconstitution. However, superior IR could protect against the negative effects of aGVHD and CMV infection on the transplant outcomes.

Adoptive therapy with cytomegalovirus-specific T cells for cytomegalovirus infection after haploidentical stem cell transplantation and factors affecting efficacy.

Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 103 copies/mL to 3.9 (range, 0-112) × 103 copies/mL after CMV-CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0-40.8), 76.8% (95% CI 70.7-82.9), and 89.5% (95% CI 85.2-93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (hazard ratio [HR] 2.29, 95% CI 1.29-4.06, p = .005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy.

Basiliximab for steroid-refractory acute graft-versus-host disease: A real-world analysis.

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD.

KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionally, we found that overexpression of KCNN4 promoted PDAC cell proliferation, migration and invasion. Conversely, the knockdown of KCNN4 attenuated the growth and motility of PDAC cells. In addition to these, knockdown of KCNN4 promoted PDAC cell apoptosis and led to cell cycle arrest in the S phase. In mechanistic investigations, RNA-sequence revealed that the MET-mediated AKT axis was essential for KCNN4, encouraging PDAC cell proliferation and migration. Collectively, these findings reveal a function of KCNN4 in PDAC and suggest it's an attractive therapeutic target and tumor marker. Our studies underscore a better understanding of the biological mechanism of KCNN4 in PDAC and suggest novel strategies for cancer therapy.