Integrating Bulk-seq and Single-cell-seq Reveals Estrogen and MAPK Pathways Associating with Neuroblastoma Outcome.

INTRODUCTION: Neuroblastoma is the most common extracranial solid tumor in children. Patients with high-risk neuroblastoma have a 5-year survival rate less than 50% after extensive treatment. Signaling pathways control cell fate decisions that dictate the behavior of tumor cells. The deregulation of signaling pathways is etiological in cancer cells. Thus, we speculated that the pathway activity of neuroblastoma contains more prognostic information and therapeutic targets. METHODS: Using a footprint-based method, we calculated the activity of fourteen pathways in neuroblastoma. Through stepwise Cox regression analyses, we established a three-gene prognostic signature whose predictive performance was evaluated by external validation. Combining a single-cell sequencing dataset, the most active pathways in high-risk neuroblastoma were found. RESULTS: We found that several pathway activities were correlated with neuroblastoma outcomes. We built a three-gene model comprising DLK1, FLT3, and NTRK1, which exhibited superior internal and external performances. We created a nomogram that combines clinical characteristics to aid in the selection and visualization of high-risk neuroblastoma patients. Furthermore, by integrating a single-cell sequencing dataset, we found that estrogen and MAPK were the most active pathways in high-risk neuroblastoma. CONCLUSION: Our findings suggest that pathway-related therapies may hold promise for the treatment of high-risk neuroblastoma.

Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed Suzuki-Miyaura Coupling.

The direct conversion of alkyl esters to ketones has been hindered by the sluggish reactivity of the starting materials and the susceptibility of the product towards subsequent nucleophilic attack. We have now achieved a cross-coupling approach to this transformation using nickel, a bulky N-heterocyclic carbene ligand, and alkyl organoboron coupling partners. 65 alkyl ketones bearing diverse functional groups and heterocyclic scaffolds have been synthesized with this method. Catalyst-controlled chemoselectivity is observed for C(acyl)-O bond activation of multi-functional substrates bearing other bonds prone to cleavage by Ni, including aryl ether, aryl fluoride, and N-Ph amide functional groups. Density functional theory calculations provide mechanistic support for a Ni0 /NiII catalytic cycle and demonstrate how stabilizing non-covalent interactions between the bulky catalyst and substrate are critical for the reaction's success.

Exhaustive Reduction of Esters Enabled by Nickel Catalysis.

We report a one-step procedure to directly reduce unactivated aryl esters into their corresponding tolyl derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC-catalyzed hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this transformation that often require the use of hazardous metal hydrides. Applications in the synthesis of -CD3-containing products, derivatization of bioactive molecules, and chemoselective reduction in the presence of other C-O bonds are demonstrated.

Nickel-Catalyzed Domino Heck-Type Reactions Using Methyl Esters as Cross-Coupling Electrophiles.

While esters are frequently used as traditional electrophiles in substitution chemistry, their application in cross-coupling chemistry is still in its infancy. This work demonstrates that methyl esters can be used as coupling electrophiles in Ni-catalyzed Heck-type reactions through the challenging cleavage of the C(acyl)-O bond under relatively mild reaction conditions at either 80 or 100 °C. With the σ-NiII intermediate generated from the insertion of acyl NiII species into the tethered C=C bond, carbonyl-retentive products were formed by domino Heck/Suzuki-Miyaura coupling and Heck/reduction pathways when organoboron and mild hydride nucleophiles are used.

Brønsted Acid Enabled Nickel-Catalyzed Hydroalkenylation of Aldehydes with Styrene and its Derivatives.

A Brønsted acid enabled nickel-catalyzed hydroalkenylation of aldehydes and styrene derivatives has been developed. The Brønsted acid acts as a proton shuttle to transfer a proton from the alkene to the aldehyde, thereby leading to an economical and byproduct-free coupling. A series of synthetically useful allylic alcohols were obtained through one-step reactions from readily available styrene derivatives and aliphatic aldehydes in up to 88 % yield and with high linear selectivity.

Iron-Catalyzed Regioselective Transfer Hydrogenative Couplings of Unactivated Aldehydes with Simple Alkenes.

An FeBr3 -catalyzed reductive coupling of various aldehydes with alkenes that proceeds through a direct hydride transfer pathway has been developed. With (i) PrOH as the hydrogen donor under mild conditions, previously challenging coupling reactions of unactivated alkyl and aryl aldehydes with simple alkenes, such as styrene derivatives and α-olefins, proceeded smoothly to furnish a diverse range of functionalized alcohols with complete linear regioselectivity.

Superiority of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Donor lymphocyte infusion (DLI) was used as salvage therapy in leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but existing results on DLI administration to acute leukemia patients were disappointing. Although increasing minimal residual disease (MRD) after HSCT had been proven to be highly indicative of posttransplant relapse, preemptive DLI (pDLI) based on MRD has not been well evaluated. STUDY DESIGN AND METHODS: We retrospectively analyzed 70 acute leukemia patients after allo-HSCT in our center between January 2005 and December 2010. Sixteen patients received pDLIs based on increasing MRD results (pDLI group), and 11 relapsed patients received therapeutic DLIs with or without chemotherapy (tDLI group). Donor lymphocytes were collected from the original donors without stimulation and infused without further manipulation. The median mononuclear cell doses and CD3+ cell doses were 1.49 × 10(8) and 5.51 × 10(7) /kg. Forty-three patients who did not receive pDLI therapy after detecting increasing MRD (no pDLI group) were also included as a comparison. RESULTS: The response rate was 100% in the pDLI group, whereas it was 63.6% in the tDLI group (p=0.019). Survival outcomes were superior in the pDLI group compared with the tDLI group (χ(2) = 14.624, p=0.000); estimated overall survival (OS) at 1 year was 93.8% with pDLI and 27.3% with tDLI. The incidence of overall acute graft-versus-host disease (aGVHD) and Grade III to IV aGVHD was higher in the pDLI group but with no significance. Patients in the "no pDLI" group showed an inferior prognosis with 1-year OS at 65.1% (95% confidence interval, 50.8%-79.4%). CONCLUSION: Our results demonstrated the efficacy and safety of pDLI and suggested that pDLI based on MRD monitoring was superior in acute leukemia patients with potential progression compared with salvage DLI administrated in overt relapse.

Collective asymmetric synthesis of (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine with tert-butanesulfinamide as a chiral auxiliary.

A collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular SN2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl3-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.

Ni-catalyzed arylation of alkynes with organoboronic acids and aldehydes to access stereodefined allylic alcohols.

A new, efficient and practical method for the three-component arylative coupling of aldehydes, alkynes and arylboronic acids has been developed through nickel catalysis. This transformation provides diverse Z-selective tetrasubstituted allylic alcohols without the use of any aggressive oragnometallic nucleophiles or reductants. Moreover, benzylalcohols are viable coupling partners via oxidation state manipulation and arylative coupling in one single catalytic cycle. This reaction features a direct and flexible approach for the preparation of stereodefined arylated allylic alcohols with broad substrate scope under mild conditions. The utility of this protocol is demonstrated through the synthesis of diverse biologically active molecular derivatives.

Regio- and chemoselective hydroamination of unactivated alkenes with anthranils via NiH-catalysis.

A NiH-catalyzed polarity-reversed hydroamination of ß,γ-, γ,δ- and δ,ε-unsaturated alkenes with electrophilic anthranils was developed. This reaction proceeds in a highly regio- and chemoselective manner to afford γ, δ and ε-arylamines bearing a carbonyl or alcohol functionality with 100% atom efficiency. Preliminary mechanistic studies indicate that the chemoselectivity is controlled by the base and the alcohol product is derived from the base-catalyzed hydrosilylation of the CO bond.

Cross-coupling reactions with esters, aldehydes, and alcohols.

Cross-coupling reactions to form biaryls and π bond addition reactions to prepare substituted carbonyls or alcohols represent two of the most frequently performed families of chemical reactions. Recent progress in catalysis has uncovered substantial overlap between these two seemingly distinct topics. In particular, esters, aldehydes, and alcohols have been shown to act as carbon-based coupling partners in a range of Ni- and Pd-catalyzed reactions to prepare amides, ketones, substituted alcohols, alkanes, and more. These reactions provide promising alternatives to commonly used stoichiometric or multi-step reaction sequences. In this feature article, a selection of these transformations will be discussed with an emphasis on the key mechanistic steps that allow these non-traditional substrates to be incorporated into cross-coupling-like catalytic cycles.

Discovery and Nanosized Preparations of (S,R)-Tylophorine Malate as Novel anti-SARS-CoV-2 Agents.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has stimulated the search for effective drugs for its prevention and treatment. Natural products are an important source for new drug discovery. Here, we report that, NK007(S,R), a tylophorine malate, displays high antiviral activity against SARS-CoV-2 with an EC50 0.03 µM in vitro, which is substantially lower than that of remdesivir (EC50: 0.8 µM in vitro), the only authorized drug to date. The histopathological research revealed that NK007(S,R) (5 mg/kg/dose) displayed a protection effect in lung injury induced by SARS-CoV-2, which is better than remdesivir (25 mg/kg/dose). We also prepared two nanosized preparations of NK007(S,R), which also showed good efficacy (EC50: NP-NK007, 0.007 µM in vitro; LP-NK007, 0.014 µM in vitro). Our findings suggest that tylophora alkaloids, isolated from the traditional Chinese medicine Cynanchum komarovii AL, offer a new skeleton for the development of anticoronavirus drug candidate.

Increased Serum Level of Interleukin-10 Predicts Poor Survival and Early Recurrence in Patients With Peripheral T-Cell Lymphomas.

Peripheral T cell lymphoma (PTCL) is an alloplasm group of aggressive and lymphoproliferative tumors with heterogeneous morphological changes of mature T cell immunophenotype. It has multiple subtypes and most of them have poor prognosis. Interleukin 10 (IL-10) is one kind of multi-cell-derived and multifunctional cytokine. It regulates the growth and differentiation of cells, participates in inflammation and immune response, plays an important role in tumor and infection, and is closely related to blood system diseases. Therefore, we implemented a retrospective study of 205 patients who were newly diagnosed with PTCL to explore the relationship between IL-10 and prognosis and early recurrence. We found patients with IL-10 ≥3.6 pg/ml achieved a lower CR rate and higher 1-year recurrence rate than patients with IL-10 <3.6 pg/ml (14.4 vs. 51.9%; 17.6 vs. 49.5%). On multivariate analysis, moreover, elevated IL-10 is an extremely important prognostic factor in PTCL, which can lead to worsening of overall survival (OS), low complete response (CR) rate and higher early relapse rate. Therefore, measurement of IL-10 levels in peripheral blood at the initial stage are useful for predicting the prognosis and helping us to make different treatment plans for individual patients. In the near future, IL-10 inhibitors or antagonists may become a new method of immunotargeting therapy for patients with PTCL.

The prognostic value of platelet-lymphocyte ratio and neutrophil-lymphocyte ratio in the treatment response and survival of patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and highly heterogeneous non-Hodgkin lymphoma (NHL). Although a few prognostic models have been put forward to predict the prognosis of PTCL, some patients with poor prognosis remain unidentified. Therefore, we conducted a retrospective study of 213 adult PTCL patients and assessed the prognostic role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in the complete response (CR) and survival of PTCL patients. Patients with PLR ≥ 232.5 achieved a lower CR rate than patients with PLR < 232.5 (18.5% vs. 56.6%, p < .001). Moreover, there was a statistical significance in CR rate between patients with NLR ≥ 3.7 and < 3.7 (31.7% vs. 60.7%, p < .001). The univariable analysis indicated that both PLR and NLR were related with worse OS. However, only PLR remained an independent prognostic indicator of OS (p = .002) by multivariable analysis.

Hypertriglyceridemia in Newly Diagnosed Acute Promyelocytic Leukemia.

The primary aim of the present retrospective study was to investigate lipid profiles and kinetics in acute promyelocytic leukemia (APL) patients. We analyzed 402 newly diagnosed APL patients and 201 non-APL patients with acute myeloid leukemia (as control). Incidence of hypertriglyceridemia in APL patients and non-APL patients was 55.82% and 28.4% (p = 0.0003). The initial levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were higher in APL patients than in control (all p < 0.0001). In APL patients, triglyceride levels were significantly increased during induction treatment with all-trans retinoic acid and arsenic. Multivariable analysis showed that age, being overweight (body mass index ≥25) and APL were independent risk factors for hypertriglyceridemia in all patients before treatment. High triglyceride levels were not significantly associated with disease-free survival or overall survival in the APL patients. In summary, in the current study triglyceride levels were significantly elevated in APL patients before treatment, and they increased during induction treatment, but there were no significant corresponding effects on survival.

Risk factors of early death in adult patients with secondary hemophagocytic lymphohistiocytosis: a single-institution study of 171 Chinese patients.

Background: Adult secondary hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome characterized by excessive activation of mononuclear-phagocytic system resulting in hyperinflammatory response. To date, the factors influencing early death of HLH are still not fully elucidated. Patients and Methods: We did a retrospective study of 171 adult patients with newly diagnosed HLH at our institution from January 2012 to April 2018. All patients' clinical features, laboratory findings, treatments and prognosis were reviewed. Results: The median age was 49 years (range, 18-88 years), and 110 (64.3%) were male. The major underlying trigger of HLH was malignancy (88/171, 51.5%), especially non-Hodgkin lymphoma. In a multivariate analysis, age ≥54 years (P = 0.002), platelet ≤39.5 × 109/L (P = 0.028), activated partial thromboplastin time (APTT) ≥54 sec (P = 0.048), triglyceride ≥3.23 mmol/L (P < 0.001), lactate dehydrogenase (LDH) ≥1300 U/L (P = 0.012) and malignancy (P = 0.001) were significantly associated with early death in HLH. Then, patients were classified into four groups according to the number of risk factors at the time of diagnosis: low risk (zero, one or two risk factors), low intermediate risk (three risk factors), high intermediate risk (four risk factors) and high risk (at least five risk factors), with the 30-day overall survival (OS) of 92.4%, 58.8%, 30.0% and 4.8%, respectively (P < 0.001). Conclusions: Patients with old age, thrombocytopenia, prolonged APTT, hypertriglyceridemia, elevated LDH and malignancy had inferior survival. It is important to identify those patients at risk of early death, which may guide treatment and reduce mortality.

Factors Affecting Early Death and Survival of Patients With Acute Promyelocytic Leukemia Treated With ATRA-Based Therapy Regimens.

PURPOSE: To perform a retrospective analysis of the prognostic relevance of clinicopathologic parameters in a well-documented cohort of patients treated with all-trans-retinoic acid (ATRA)-based induction regimens in order to discover which indicators can predict a high risk of early death (ED) and patient survival. PATIENTS AND METHODS: We analyzed data of 288 newly diagnosed adult acute promyelocytic leukemia patients in Hangzhou, China. The median follow-up time was 32 months (range, 6-78 months). RESULTS: The 3-year disease-free and overall survival rates were 90.83% and 91.69%, respectively. In the multivariable analysis, older age (≥ 60 years) was the only independent risk factor for ED (hazard ratio [HR] = 15.057; P = .004). High white blood cell count was not a risk factor for ED (P = .055), but it was for relapse (HR = 2.7; P = .009). FLT3 mutation (HR = 3.9; 95% confidence interval, 1.4 to 10; P = .007) and older age (≥ 60 years) (HR = 5.3; 95% confidence interval, 2.4 to 11; P < .001) were prognostic factors for poorer disease-free and overall survival. Interestingly, CD15 negativity (HR = 0.23; P = .049) was a prognostic factor for relapse. The ED rate was 5.9% (17/288 patients). CONCLUSION: The perceived impact of the identification of these high-risk factors should be described in order to decide whether any modifications to treatment strategy should be entertained.

Novel homobarringtonie-containing therapy for the treatment of patients with primary acute myeloid leukemia that are resistant to conventional therapy.

The current study investigated the efficacy and safety of a novel treatment regime consisting of homobarringtonie, cytosine arabinoside and etoposide (HCE) for the treatment of primary acute myeloid leukemia (AML). In the present study, 141 patients diagnosed with AML were divided into the HCE (n=47) and the conventional AML therapy, consisting of idamycin combined with cytarabine (IA; n=94), treatment groups. The measured patient outcome parameters were the emission and response rates, as well as medication-induced adverse events, with a median follow-up time of 28 months. There was no significant difference in the 3-year relapse-free survival rate between the HCE and IA treatment groups. The occurrence and severity of hematological or non-hematological toxicity did not differ between the two groups. However, of the 26 patients that demonstrated a poor response to the IA treatment, 19 cases were administered the HCE treatment and 14 of these patients achieved complete remission (CR). Of the 10 patients that demonstrated a poor response to the HCE treatment, 8 patients were administered the IA treatment and 7 of these achieved CR. Therefore, HCE may be an effective treatment regimen for patients with primary AML. As there was no cross-resistance between the HCE and IA regimens, HCE may be an alternative option for patients that respond poorly to IA induction therapy.

Risk factors and clinical characteristics of non-promyelocytic acute myeloid leukemia of intracerebral hemorrhage: A single center study in China.

BACKGROUND: Although high mortality in patients with acute leukemia (AL) is associated with intracranial hemorrhage (ICH), the clinical features and pathogenesis of AL patients with cerebral hemorrhage are not well known. METHODS: We diagnosed 90 patients with ICH from a total of 1467 patients with non-promyelocytic AL who had been hospitalized in the First Affiliated Hospital of Medical School of Zhejiang University from January 2010 to October 2015. Moreover, the risk factors of ICH death were evaluated. RESULT: Median age at ICH was 51years old, in which men accounted for 52.2%. They also accounted for 85.6% of acute myeloid leukemia. The relative incidence of ICH was the highest in M2 and M5 (60.1%). ICH presented with higher peripheral blood white blood cell count (WBC) (P<0.001), lower peripheral platelet counts (P<0.001), lower albumin (P<0.001), lower fibrous protein (P<0.001) and prolongation of prothrombin time (P<0.001) compared to those observed in the patients of NICH group; multivariate analysis, independent risk factors for death in patients with ICH include: WBC≥30.00×109/l and prothrombin time≥12.91 s. CONCLUSIONS: Leukocytosis and coagulation dysfunctions might be the main pathogenesis of acute leukemia complicated with cerebral hemorrhage.

Clinical and histological features of primary testicular diffuse large B-cell lymphoma: a single center experience in China.

Primary testicular lymphoma (PTL) is a rare and aggressive form of extranodal lymphoma. Approximately 80-98% of PTLs are diffuse large B-cell lymphoma (PT-DLBCL). The prognosis of DLBCL patients has improved with the addition of rituximab to systemic chemotherapy, but outcomes of PT-DLBCL remain poor. This may be explained by the high rate of relapse in the central nervous system (CNS) and contralateral testis. We analyzed 1,132 newly diagnosed DLBCL patients (37 with PT-DLBCL) who were treated at our hospital between January 2009 and December 2014. Twenty-five patients finished follow-up. We analyzed clinical characteristics, response to chemotherapy, overall survival, and relapse in the CNS and contralateral testis. All patients underwent orchiectomy. The median age was 60 (range: 43-82) years. Eleven patients had stage III/IV disease. Five patients experienced CNS relapse, and three experienced relapse in the contralateral testis. Median overall survival (OS) was not reached at the time of reporting. The 3-year OS rate was 57%. None of the nine patients who received radiotherapy to the contralateral testis experienced relapse in that location. Intrathecal prophylaxis did not reduce the risk of CNS relapse. All five patients who experienced CNS relapse had the germinal center B-cell-like subtype of DLBCL.