Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia.

PURPOSE: Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL. METHODS: NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness. RESULTS: Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival. CONCLUSION: Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

The mechanism of STING autoinhibition and activation.

2',3'-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2',3'-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.

Clinical characteristics and prognosis of patients with co-existing follicular lymphoma and diffuse large B-cell lymphoma components in rituximab era.

PURPOSE: This single-centre study aimed to determine the clinicopathological characteristics and prognosis for patients with co-existing FL and DLBCL components (FL/DLBCL). METHODS: We retrospectively analysed the clinical characteristics and prognosis of patients diagnosed with FL/DLBCL (n = 56) and with pure FL (n = 260) or de novo DLBCL (n = 812) (controls) between January 2013 and December 2021. RESULTS: The median age of patients with FL/DLBCL was 52 years. The amount of the DLBCL component ranged from 5 to 95%. Among the 56 FL/DLBCL cases analysed, 67.9% were of germinal centre B-cell (GCB) origin, 26.8% non-GCB origin, and 5.3% were unclassified. The clinical features of patients with FL/DLBCL were intermediate, falling between those of FL and DLBCL. Propensity-score matching was performed for patients with similar baseline characteristics who were receiving the rituximab plus cyclophosphamide, doxorubicin or epirubicin, vindesine, and prednisone (R-CHOP) regimen. Patients with FL/DLBCL showed inferior outcomes compared to those with FL, with a lower complete remission (CR) rate, progression-free survival (PFS), and overall survival (OS). Bone marrow involvement and B symptoms were identified as independent adverse prognostic factors for PFS among patients with FL/DLBCL. Patients with FL/DLBCL presented a lower CR rate and PFS but similar OS to those with DLBCL when receiving the R-CHOP regimen. CONCLUSION: Patients with FL/DLBCL showed inferior treatment response and survival than those with pure FL and had a lower CR rate and PFS, but similar OS to those with DLBCL in the rituximab era.

Hypomethylating agents combined with low-dose chemotherapy for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: a real-world clinical experience.

This study aimed to assess the efficacy and safety of hypomethylating agent (HMA)-based regimens in the treatment of older adult patients with acute myeloid leukaemia (AML), unfit for standard induction chemotherapy. Treatment outcomes and prognostic factors of 140 older adult patients with AML who were unfit for intensive chemotherapy and were treated with HMA-based therapies were retrospectively analysed. The median age of the group was 70 years, and poor-risk cytogenetics and secondary/treatment-related AML (s/t-AML) accounted for 45.6% and 34.3% of these patients, respectively. The overall response rate was 48.6%, and 40.1% for patients who achieved complete remission (CR) or CR with incomplete blood count recovery. The median overall survival (OS) was 10.4 months, and the 1-, 2-, and 5-year OS rates were 42.6%, 19.9%, and 4.9%, respectively. Early mortality accounted for 4.3% of all cases, and infection occurred in 87.1% of all patients during induction therapy. Patients who received HMA and low-dose chemotherapy presented with significantly superior response and long-term survival rates compared to those who received HMA alone. They also showed comparable outcomes to those treated with the azacitidine plus venetoclax protocol. Low-dose chemotherapy in combination with decitabine or azacitidine showed a similar response rate and prognosis. Age ≥ 75years and a white blood cell (WBC) count ≥ 10 × 109 cells/L were identified as independent adverse prognostic factors for OS, while poor-risk cytogenetics, percentage of bone marrow blasts, and s/tAML had no significant impact on OS when patients were treated with HMA-based regimens. In conclusion, HMA combined with low-dose chemotherapy was effective and safe in older adults with AML who were unfit for intensive chemotherapy, and no difference was observed between decitabine and azacitidine.

SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry.

After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27-retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.

Clinical characteristics and survival of extranodal natural killer/T-cell lymphoma: a single-center 12-year retrospective analysis.

The characteristics and survival of 218 patients with extranodal natural killer/T-cell lymphoma (ENKTCL) were analyzed in this retrospective study. The median progression-free survival (PFS) and overall survival (OS) were 10.9 months and 50.5 months, respectively. Sequential chemoradiotherapy achieved a 74.5% overall response rate (ORR) and a 30.9% 5-year PFS rate in patients with localized stage. Asparaginase-containing protocols demonstrated superior prognosis in advanced cases, with a median FPS at 5.7 months, compared to 1.9 months without asparaginase. Initial treatment with P-GEMOX regimens showed superior ORR and PFS compared to the SMILE regimen, with lower toxicities. Hematopoietic stem cell transplantation (HSCT) improved the PFS and OS of refractory or relapsed (R/R) cases. PD-1/PD-L1 antibody could achieve a median PFS at 4.0 months and a median OS at 14.6 months in R/R patients for whom salvage therapies failed. High-risk PINK-E score was the only independent adverse prognostic factor for PFS and OS.

First Report of Dieback Caused by Lasiodiplodia pseudotheobromae on Ormosia pinnata in China.

Ormosia pinnata (Lour.) Merr. is an important tree used for landscape and plant recovery of barren slopes in China. During an investigation of plant disease on landscape trees in 2018, a dieback was observed on O. pinnata trees in Guangzhou, Guangdong Province, China. Symptoms were characterized by initial dryness of the twigs and eventual death of the whole branch of the tree. Isolations from symptomatic branches yielded 13 isolates including two main morphotypes. Pathogenicity tests showed that isolate GDOP1 from Type I caused dieback of O. pinnata. Based on morphological characteristics and molecular analysis of the internal transcribed spacer rDNA (ITS1-5.8S-ITS2) and partial sequence of the translation elongation factor 1α (EF1-α), the fungus causing dieback on O. pinnata was identified as Lasiodiplodia pseudotheobromae. This is the first report of L. pseudotheobromae infecting O. pinnata in the world.

Immunohistochemical overexpression of BCL-2 protein predicts an inferior survival in patients with primary central nervous system diffuse large B-cell lymphoma.

This study was designed to analyze the clinical characteristics and prognostic value of c-MYC and BCL-2 proteins expression in patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL).82 patients newly diagnosed with PCNS-DLBCL, from January 2008 to November 2018, were enrolled in this study. Clinical characteristics, immunohistochemical features, laboratory examinations, and treatment outcome were analyzed among these patients.Among these 82 cases, 45 were males (54.9%) and 37 were females (45.1%). Age ranged from 16 to 78 years old, and 29 patients (35.4%) were elder than 60 years old, with median age at 57 years old. According to Hans classification, 25 were accounted for origin of germinal center B-cell (GCB) subtype (30.5%) and 49 were accounted for non-GCB subtype (59.8%), respectively. Eight patients were unclassified due to lack of detailed pathological results. The median survival of these 82 patients was 30 months, and 1-year, 3-year, and 5-year overall survival (OS) rate was 59.7%, 44.6%, and 34.1%, respectively. Patients treated with sequential HD-MTX based chemotherapies showed a superior prognosis than those without. In combination with rituximab, the outcome was further improved. The median OS was 55 months in HD-MTX + R group, 27 months in HD-MTX group, and 9 months in other groups, respectively. Univariate analysis identified age ≥60, ECOG score ≥ 2 points, and overexpression of BCL-2 protein (≥85%) were adverse prognostic factors for OS. Co-expression of c-MYC (≥40%) and BCL-2 (≥50%) proteins was associated with poor ECOG score, high Ki-67 expression, and trended towards an inferior outcome. Gender, lesion location, number of lesions, lactic dehydrogenase (LDH), cell of origin, BCL-6 protein expression, expression of c-MYC protein alone and Ki-67 ≥85% had no significant impact on OS.In patients with PCNS-DLBCL, age ≥60 years old, ECOG score ≥2 points, and overexpression of BCL-2 protein (≥85%) were associated with a poor survival. HD-MTX based chemotherapies in combination with rituximab could improve the prognosis.

The clinical significance of Epstein-Barr virus DNA in peripheral blood mononuclear cells in patients with non-Hodgkin lymphoma.

The aim of the study was to determine the clinical significance of EBV DNA in the peripheral blood mononuclear cells (PBMCs) from the patients with non-Hodgkin lymphoma (NHL). Newly diagnosed patients with NHL were enrolled in the study (n = 328), and clinical data retrospectively analyzed. EBV DNA was detectable in 34.8% of patients, and the positivity rate was 51.6% for T/NK cell subtype and 24.3% for B cell subtype (p < .001). In diffuse large B cell lymphoma (DLBCL), extranodal NK/T-cell lymphoma, nasal type (ENKTL), peripheral T-cell lymphoma not otherwise classified (PTCL.NOS), or angioimmunoblastic T cell lymphoma (AITL), positive EBV DNA before treatment was associated with more risk factors with prognostic significance, including older age, advanced stage, extranodal involvement, bone marrow infiltration, elevated LDH, and B symptoms, and with poor prognosis.

The outcome and prognostic factors of 248 elderly patients with acute myeloid leukemia treated with standard-dose or low-intensity induction therapy.

The prognosis of elderly patients with acute myeloid leukemia (AML) is poor, and the recommendation of standard-dose or low-intensity induction regimen for these patients remains controversial. We retrospectively analyzed treatment outcome and prognostic factors of elderly AML patients who had received either standard-dose or low-intensity induction regimens.Two hundred forty-eight elderly AML patients with good Eastern Cooperative Oncology Group performance status (ECOG PS ≤ 2) received one of three regimens for induction in this study: standard-dose cytarabine plus idarubicin (IA; n = 144) or daunorubicin (DA; n = 42); low-intensity cytarabine, aclarubicin, and granulocyte colony-stimulating factor (G-CSF) (CAG; n = 62).After first induction treatment cycle, the overall complete remission (CR) rate was 42.7%. Patients in IA group had a higher CR rate than in DA or CAG group (49.3%, 35.7%, and 32.3%, respectively; P = 0.046). The 1-year, 3-year, and 5-year overall survival (OS) rates were 42.2%, 18.9%, and 13.5% for these 248 patients, with median survival of 9.2 months. Long-term survival of IA group was better than DA or CAG group. The 1-year, 3-year, and 5-year OS rates of IA group were 45.9%, 23.5%, and 19.4%, respectively, as compared to 39.8%, 8.3%, and estimated 2.4% in DA group, and 34.9%, 15.9%, and 6.3% in CAG group, respectively. Early induction mortality and 2-year relapse rates showed no difference among 3 groups. Univariate analysis and multivariate analysis identified lactic dehydrogenase (LDH) more than two times of upper normal limit at diagnosis and nonremission after first induction cycle as adverse prognostic factors for OS. A simple and valid scoring model was constructed for risk stratification and prediction of long-term survival of elderly AML patients.Standard-dose IA regimen could improve the prognosis of elderly AML patients with good performance status compared with standard-dose DA or low-intensity CAG regimen. All prognostic factors and risk assessment should be considered to ensure that each patient receives the suitable individualized treatment.

Examining the Effects of Biochar Application on Soil Phosphorus Levels and Phosphatase Activities with Visible and Fluorescence Spectroscopy

Biochar could be got from crop straw which contain rich carbon under oxygen free or oxygen limited conditions at low temperature. The application of biochar into soil is beneficial to ease the pressure of handling straw, reduce pollution, reduce greenhouse gas emissions and improve soil quality. This study was carried out in a cornfield containing meadow brown soil at the lower reaches of Liao River which was treated with different amounts of biochar (0, 360, 1 800, 3 600 kg·ha-1) and fertilizer. We investigated the contents of soil available phosphorus (AP), organic P (OP) and total P (TP). We also investigated the enzyme activities of soil acid phosphatase (AcP), alkaline phosphatase (AlP) and phosphodiesterase (PD) via a fluorescence spectroscopy method by using a fluorescent conjugated polymer as the substrate. Soil AP contents increased drastically with the increasing application of biochar, whereas the OP and TP contents exhibited little change. The increase in AP contents was ascribed to the introduction of P into the soil via biochar. Soil AlP and PD activities increased with increasing biochar application. Soil AcP activity increased significantly after the application of the appropriate amount of biochar (1 800 kg·ha-1), whereas it was inhibited by the application of high levels of biochar (3 600 kg·ha-1), perhaps due to the intrinsic alkalinity of biochar. The effect of Biochar inputs on soil phosphorus element and phosphatase activity is the comprehensive embodiment of the soil physical properties, chemical properties, and microbial community structure and metabolic capacity. We should further study such item. The fluorescent microplate method used in this study has many advantages, such as accuracy, rapidness and simple to perform.

Effect of Exogenous Phytase Addition on Soil Phosphatase Activities: a Fluorescence Spectroscopy Study.

The utilization of organic phosphorus (P) has directly or indirectly improved after exogenous phytase was added to soil. However, the mechanism by which exogenous phytase affected the soil phosphatases (phosphomonoesterase and phosphodiesterase) activities was not clear. The present work was aimed to study red soil, brown soil and cinnamon soil phosphomonoesterase (acid and alkaline) (AcP and AlP) and phosphodiesterase (PD) activities responding to the addition of exogenous phytase (1 g phytase/50 g air dry soil sample) based on the measurements performed via a fluorescence detection method combined with 96 microplates using a TECAN Infinite 200 Multi-Mode Microplate Reader. The results indicated that the acid phosphomonoesterase activity was significantly enhanced in red soil (p≤0. 01), while it was significantly reduced in cinnamon soil; alkaline phosphomonoesterase activity was significantly enhanced in cinnamon soil (p≤ 0. 01), while it was significantly reduced in red soil; phosphodiesterase activity was increased in three soils but it was significantly increased in brown soil (p≤0. 01) after the addition of exogenous phytase. The activities still remained strong after eight days in different soils, which indicated that exogenous phytase addition could be enhance soil phosphatases activities effectively. This effect was not only related to soil properties, such as pH and phosphorus forms, but might also be related to the excreted enzyme amount of the stimulating microorganism. Using fluorescence spectroscopy to study exogenous phytase addition influence on soil phosphatase activities was the first time at home and abroad. Compared with the conventional spectrophotometric method, the fluorescence microplate method is an accurate, fast and simple to use method to determine the relationships among the soil phosphatases activities.

[Mandibular incisive canal by cone beam CT].

OBJECTIVE: This study was conducted to determine the three-dimensional structure, course, and adjacent structure of the mandibular incisive canal (MIC) to ensure safety of dental implantation by cone beam CT (CBCT). METHODS: The CBCT images of the bilateral mandibles of 80 patients were retrospectively studied. The diameters of the mandibular incisive canal and the location in the adjacent structure were determined, including the distances between the MIC and the buccal and lingual plates of the alveolar bone, the inferior border of the mandible and the tooth apex, and the horizontal plane of the mental foramen. RESULTS: Approximately 78.75% (63 cases) of the CBCT scans showed the presence of the MIC with a mean diameter of 1.21 mm +/- 0.29 mm. The distances from the canal to the inferior border of the mandible and to the tooth apex were 7.82 mm +/- 1.86 mm and 7.24 mm +/- 2.82 mm, respectively. The distances between the canal and the buccal plate as well as between the canal and the lingual plate of the alveolar bone were 3.80 mm +/- 1.37 mm and 4.45 mm +/- 1.34 mm, respectively. The distance from the canal to the horizontal plane of the mental foramen was 5.62 mm +/- 2.21 mm. CONCLUSION: CBCT could clearly show the three-dimensional structure, course, and adjacent structure of the MIC. Therefore, this technique could provide guidance for dental implantation in clinical applications.

[Efficacy of CALLG2008 protocol in treatment of adult acute lymphoblastic leukemia: a single center analysis].

CALLG2008 Protocol is sequential chemotherapy for adult acute lymphoblastic leukemia (ALL) established by Collaborative Group of adults acute lymphoblastic leukemia. It is emphasized that comprehensive treatment of adult ALL according to risk stratification is rather important. This study was purposed to evaluate the therapeutic efficacy of CALLG2008 for adult ALL. The clinical data of adult ALL patients of ≥ 14 years old diagnosed and treated by CALLG2008 Protocol were collected from May 1, 2009 to December 31, 2011 in Fujian Medical University Union Hospital, and the efficacy was analyzed. The results showed that 31 out of 33 cases of ALL achieved CR, the CR rate was up to 93.9%, the PR rate was 3.1%, and the total response rate was 97%. There were no uncontrolled severe toxicities, and no early deaths were observed. The overall survival (OS) at 1 year was only 66.7%,the relapse rate was 43.8% and the 1-year mortality was 33.3 %. This may be related with no-enough compliance, no-enough economical support and short follow-up time of the patients. The risk factor analysis showed that WBC level in newly diagnosed patients may influence the OS and relapse-free survival (RFS) of ALL. It is concluded that CALLG2008 protocol applied to adult ALL has a high remission quality and low mortality rate during the induction. The disease free survival (DFS) needs to be observed longer. It is essential to carry out MRD monitoring to determine the early recurrence and improving the long-term efficacy.

[A comparison of the clinical anesthetic efficacy of articaine infiltration and lidocaine blocking for microport extraction of impacted mandibular molar].

OBJECTIVE: To compare the clinical efficacy of the infiltration anesthesia with primacaine and the nerve blocking anesthesia with lidocaine for microport extraction of impacted lower third molar. METHODS; 104 chosen patients had both sides of impacted lower third molars extracted in this study. Patients were given local anesthesia with either primacaine or lidocaine randomly at each side, and then underwent microport extraction. Clinical factors including effective proportion (EP), effecting time point (ETP), visual analogue scale of pain (VASp), alteration of systolic pressures (ASP) and analgesia duration (AD) were evaluated statistically by means of paired t-test. RESULTS: The EP of experimental group was higher than the control group (P = 0.024). The ETP of soft tissue and alveoli-dental pulp was (1.04 +/- 0.21), (2.44 +/- 2.60) min in the experimental group, and much earlier than that of the control group (P = 0.002, P = 0.032). The VASp and ASP of experimental group were lower than the control group (P = 0.041, P = 0.018). AD was (103.6 +/- 35.5) min, and higher than the control group (P = 0.04). CONCLUSION: The infiltration anesthesia with primacaine has been proven to be a easier, reliable and quick-acting method. We suggest it an alternative method replacing the 2% lidocaine blocking during microport extraction of impacted lower third molar.