Publications by authors named "Yucai Wang"

144 Publications

Patterns of therapy initiation during the first decade for patients with follicular lymphoma who were observed at diagnosis in the rituximab era.

Blood Cancer J 2021 Jul 17;11(7):133. Epub 2021 Jul 17.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Immediate treatment for asymptomatic, low-tumor burden follicular lymphoma (FL) has not shown an overall survival benefit over "watch and wait" (W/W) strategy. We estimated incidence of treatment initiation at specific time points and assessed its association with the presence of any criteria such as GELF, BNLI, GITMO at diagnosis. FL patients managed by W/W strategy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE between 2002 and 2015. Cumulative incidence estimates of treatment initiation were calculated using transformation (as the first event) and death as competing risks. 401 FL patients were identified on W/W strategy. At a median follow-up of 8 years, 256 (64%) initiated treatment. For patients on the W/W strategy for 5 years, the likelihood of treatment initiation in the next 5 years was 12% compared to 43% at diagnosis unlike transformation rates which remained steady. Patients with any of popular treatment criteria at diagnosis did not have increased therapy initiation rates (44% vs. 42%) during the first 5 years or lymphoma-related death rates at 10 years (6% vs. 7%). Identifying biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients.
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http://dx.doi.org/10.1038/s41408-021-00525-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286048PMC
July 2021

Phototherapy Facilitates Tumor Recruitment and Activation of Natural Killer T cells for Potent Cancer Immunotherapy.

Nano Lett 2021 Jul 15. Epub 2021 Jul 15.

Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.

Adoptively transferred natural killer T (NKT) cells confer distinct cancer surveillance without causing obvious side effects, making them a promising candidate for cancer immunotherapy. However, their therapeutic efficacy is limited by inefficient tumor infiltration and inadequate activation in an immunosuppressive tumor microenvironment. To overcome these obstacles, we develop a strategy of using photothermal therapy (PTT) to promote the antitumor ability of adoptively transferred NKT cells. The transferred NKT cells are efficiently recruited to PTT-treated tumors in response to PTT-created inflammation. Moreover, PTT treatment promotes the activation of NKT cells and enhances the NKT cell-initiated immune cascade. As a consequence, the combined therapy of PTT plus NKT cell transfer exhibits excellent growth inhibition of local tumors. Moreover, it efficiently rejects distant tumors and elicits long-term immunological memory to prevent tumor recurrence. Overall, the current study opens new paths to the clinical translation of NKT cells for cancer immunotherapy.
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http://dx.doi.org/10.1021/acs.nanolett.1c02238DOI Listing
July 2021

Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18.

Med Microecol 2020 Sep 28;5:100023. Epub 2020 Sep 28.

The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

The ongoing global pandemic of COVID-19 disease, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly infect lung epithelial cells, and spread mainly through respiratory droplets. However, recent studies showed potential intestinal infection of SARS-CoV-2, implicated the possibility that the intestinal infection of SARS-CoV-2 may correlate with the dysbiosis of gut microbiota, as well as the severity of COVID-19 symptoms. Here, we investigated the alteration of the gut microbiota in COVID-19 patients, as well as analyzed the correlation between the altered microbes and the levels of intestinal inflammatory cytokine IL-18, which was reported to be elevated in the serum of in COVID-19 patients. Comparing with healthy controls or seasonal flu patients, the gut microbiota showed significantly reduced diversity, with increased opportunistic pathogens in COVID-19 patients. Also, IL-18 level was higher in the fecal samples of COVID-19 patients than in those of either healthy controls or seasonal flu patients. Moreover, the IL-18 levels were even higher in the fecal supernatants obtained from COVID-19 patients that tested positive for SARS-CoV-2 RNA than those that tested negative in fecal samples. These results indicate that changes in gut microbiota composition might contribute to SARS-CoV-2-induced production of inflammatory cytokines in the intestine and potentially also to the onset of a cytokine storm.
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http://dx.doi.org/10.1016/j.medmic.2020.100023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832617PMC
September 2020

Clinical and Functional Characterization of Atypical / Mutations in Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Jun 11. Epub 2021 Jun 11.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Mutations in () predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all mutations have similar impact, and atypical mutations beyond those in standard guidelines exist.

Experimental Design: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical variants. Using an cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and xenograft models of transduced isogenic clones, we assessed signaling changes across mutations.

Results: exon 2, extended , and atypical mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no codon 117/146 and only one codon 59 mutation was noted. Atypical mutations had worse overall survival than wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; = 0.014). We functionally characterized 114 variants with the FACT assay. All exon 2 and extended mutations appeared activating. Of 57 atypical variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts.

Conclusions: We provide best available evidence to guide treatment when atypical variants are identified. L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included variants and functionally relevant.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0180DOI Listing
June 2021

Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome.

Blood Cancer J 2021 May 10;11(5):86. Epub 2021 May 10.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th-75th], 0.107 [0.070-0.209] vs. 0.233 [0.111-0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.
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http://dx.doi.org/10.1038/s41408-021-00477-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110984PMC
May 2021

The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL.

Blood 2021 07;138(2):149-159

Division of Hematology, Stanford University School of Medicine, Palo Alto, CA.

The utility of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age, 64 years; 65% men) seen at Mayo Clinic between 1 January 2001 and 1 October 2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/y for MBL (median, not reached) and 5%/y for Rai 0 CLL (median, 10.4 years). Among patients with low, intermediate, and high/very high-risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, P< .0001 (c-statistic = 0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, P< .0001 (c-statistic = 0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 × 109/L increase: 1.31; P< .0001) and shorter OS (HR: 1.1; P = .02). The OS of the entire cohort was similar to that of the age- and sex-matched general population of Minnesota (P = .17), although Rai 0 CLL patients with high and very high-risk CLL-IPI score had significantly shorter OS (P= .01 and P= .0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an end point not affected by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.
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http://dx.doi.org/10.1182/blood.2020009813DOI Listing
July 2021

Effects of betaine on Nonalcoholic liver disease.

Nutr Res Rev 2021 Apr 5:1-30. Epub 2021 Apr 5.

Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases,Ministry of Education, Gannan Medical University, Ganzhou, 341000, China.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, and the challenge of prevention and treatment is increasing. The "multiple hits" hypothesis of multiple insults, such as dietary fat intake, de novo lipogenesis, insulin resistance, oxidative stress, mitochondrial dysfunction, gut dysbiosis and hepatic inflammation, can provide a more accurate explanation of the pathogenesis of NAFLD. Betaine plays important roles in regulating the genes associated with NAFLD through anti-inflammatory effects, increased free fatty oxidation, anti-lipogenic effects, and improved insulin resistance and mitochondrial function; however, the mechanism of betaine remains elusive.
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http://dx.doi.org/10.1017/S0954422421000056DOI Listing
April 2021

Molybdenum derived from nanomaterials incorporates into molybdenum enzymes and affects their activities in vivo.

Nat Nanotechnol 2021 Jun 18;16(6):708-716. Epub 2021 Feb 18.

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, China.

Many nanoscale biomaterials fail to reach the clinical trial stage due to a poor understanding of the fundamental principles of their in vivo behaviour. Here we describe the transport, transformation and bioavailability of MoS nanomaterials through a combination of in vivo experiments and molecular dynamics simulations. We show that after intravenous injection molybdenum is significantly enriched in liver sinusoid and splenic red pulp. This biodistribution is mediated by protein coronas that spontaneously form in the blood, principally with apolipoprotein E. The biotransformation of MoS leads to incorporation of molybdenum into molybdenum enzymes, which increases their specific activities in the liver, affecting its metabolism. Our findings reveal that nanomaterials undergo a protein corona-bridged transport-transformation-bioavailability chain in vivo, and suggest that nanomaterials consisting of essential trace elements may be converted into active biological molecules that organisms can exploit. Our results also indicate that the long-term biotransformation of nanomaterials may have an impact on liver metabolism.
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http://dx.doi.org/10.1038/s41565-021-00856-wDOI Listing
June 2021

Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma.

Blood Cancer J 2021 01 7;11(1). Epub 2021 Jan 7.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Primary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index (P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P < 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P < 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% (P = 0.48) and OS of 57% vs 71% vs 69% (P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.
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http://dx.doi.org/10.1038/s41408-020-00394-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791108PMC
January 2021

Voluntary-Opsonization-Enabled Precision Nanomedicines for Inflammation Treatment.

Adv Mater 2021 Jan 9;33(3):e2006160. Epub 2020 Dec 9.

Institutes for Life Sciences, School of Biomedical Sciences and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction, Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangdong, 510006, P. R. China.

Nanomedicines that target specific blood cells represent an emerging strategy to improve drug biodistribution. However, the protein corona usually disrupts nanomedicine targeting to cells and tissues. Herein, instead of exploring synthetic methods to mitigate the impact of the protein corona, its natural interactions with blood cells are leveraged and turn the protein corona into an active ingredient in treating lung inflammation. It is discovered that molecularly engineered liposomes with inverse phosphocholine lipids rapidly enrich complement fragment iC3b by "voluntary opsonization," which triggers neutrophil hijacking through complement receptor 3 phagocytosis. This neutrophil targeting is cell-state dependent as only those activated by acute inflammation display efficient neutrophil reconstruction. The liposome-loaded neutrophils migrate across the alveolar-capillary barrier, accumulate in the inflamed lung parenchyma within hours, and release their payloads to kill the bacteria. This work shows that, in addition to biological cells, the protein corona can be a new platform for active and precision nanomedicine.
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http://dx.doi.org/10.1002/adma.202006160DOI Listing
January 2021

Re-detectable positive SARS-CoV-2 RNA tests in patients who recovered from COVID-19 with intestinal infection.

Protein Cell 2021 03 26;12(3):230-235. Epub 2020 Sep 26.

The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

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http://dx.doi.org/10.1007/s13238-020-00778-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518948PMC
March 2021

Disease Flare During Temporary Interruption of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia.

Oncologist 2020 11 20;25(11):974-980. Epub 2020 Sep 20.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Background: Approximately 25% of patients with chronic lymphocytic leukemia (CLL) experience a flare of disease following ibrutinib discontinuation. A critical question is whether this phenomenon may also occur when ibrutinib is temporarily held. This study aimed to determine the frequency and characteristics of disease flares in this setting and assess risk factors and clinical outcomes.

Materials And Methods: We identified all patients with CLL seen at Mayo Clinic between October 2012 and March 2019 who received ibrutinib. Temporary interruptions in treatment and associated clinical findings were ascertained.

Results: Among the 372 patients identified, 143 (38%) had at least one temporary interruption (median 1 hold, range 1-7 holds) in treatment. The median duration of interruption was 8 days (range 1-59 days) and the most common indication was periprocedural. Among the 143 patients with ≥1 hold, an associated disease flare was seen in 35 (25%) patients: mild (constitutional symptoms only) in 21 patients and severe (constitutional symptoms with exam/radiographic findings or laboratory changes) in 14 patients. Disease flare resolved with resuming ibrutinib in all patients. Predictive factors of disease flare included progressive disease at time of hold and ≥ 24 months of ibrutinib exposure. The occurrence of disease flare with an ibrutinib hold was associated with shorter event-free survival (hazard ratio 2.3; 95% confidence interval 1.3-4.1; p = .007) but not overall survival.

Conclusion: Temporary interruptions in ibrutinib treatment of patients with CLL are common, and one quarter of patients who held ibrutinib in this study experienced a disease flare. Resolution with resuming ibrutinib underscores the importance of awareness of this phenomenon for optimal management.

Implications For Practice: Ibrutinib is a very effective treatment for chronic lymphocytic leukemia (CLL) but needs to be taken continuously. Side effects, such as increased bleeding risk with procedures, require temporary interruptions in this continuous treatment. Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well. Importantly, management with restarting ibrutinib led to quick clinical improvement. Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease.
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http://dx.doi.org/10.1634/theoncologist.2020-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648348PMC
November 2020

Are pyridinium ylides radicals?

Chem Commun (Camb) 2020 Sep;56(76):11287-11290

Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230026, China.

Pyridinium ylides are usually considered nucleophiles that can undergo various reactions involving electron pairs. However, it was found that ylides resulting from deprotonation of N-alkyl-substituted pyridinium salts exhibit radical characters, with no discernable NMR signals but decent EPR spectra in both solution and the solid state. An observed correlation between lowered π* energy level of the pyridinium ring and increased EPR activity indicates that thermally induced electron-transfer processes could be involved, where the variable-temperature EPR spectrum indicates a singlet ground state and a thermally activated triplet state for the ylide. The fact that the high-resolution mass spectrum confirms the presence of oligomers of a less sterically hindered pyridinium ylide further points to a radical mechanism.
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http://dx.doi.org/10.1039/d0cc04604cDOI Listing
September 2020

Quantifiable Polymeric Fluorescent Ratiometric γ-ray Chemosensor.

ACS Appl Mater Interfaces 2020 Sep 2;12(37):42210-42216. Epub 2020 Sep 2.

Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.

Detection of γ-rays is of vital significance in various areas such as high-energy physics, nuclear medicine, national security, and space exploration. However, many current spectrometry methods are based on ionization effects, which are limited to electron counting and related techniques such as ionization-induced luminescence. Herein, we report an alternative, quantifiable γ-ray chemosensor based on a secondary effect from this ionizing radiation, that is, it was discovered that poly(methyl methacrylate) (PMMA) and polyvinyl chloride (PVC) are more sensitive to a γ-ray-induced acid generation process by surveying a series of commercially available polymers. Accordingly, a pH-sensitive fluorescent quinoline derivative is designed and embedded in PMMA or PVC films, which exhibits dramatic emission shift from blue (λ = 460-480 nm) to red (λ = 570-620 nm) upon exposure to γ-irradiation. A linear response of ratiometric fluorescence intensity (/) to γ-ray dosage in a wide range (80-4060 Gy) was established, which can be used as a practical visual dosimeter complementary to current techniques.
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http://dx.doi.org/10.1021/acsami.0c13886DOI Listing
September 2020

Betaine prevented high-fat diet-induced NAFLD by regulating the FGF10/AMPK signaling pathway in ApoE mice.

Eur J Nutr 2021 Apr 17;60(3):1655-1668. Epub 2020 Aug 17.

Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular DiseasesMinistry of Education, Gannan Medical University, Ganzhou, 341000, China.

Purpose: Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in developing countries. The pathogenesis is complex, and there is currently no effective treatment. Betaine is an essential intermediate in choline catabolism and an important component of the methionine cycle. Betaine deficiency is associated with NAFLD severity, and its mechanism needs to be further elaborated.

Methods: In this study, an NAFLD mouse model was established by feeding ApoE mice a high-fat diet. The effects of betaine on NAFLD were investigated, including its mechanism.

Results: In this study, after treatment with betaine, blood lipid levels and liver damage were significantly decreased in the NAFLD mouse model. The fat infiltration of the liver tissues of high-fat diet (HFD)-fed mice after betaine administration was significantly improved. Betaine treatment significantly upregulated AMP-activated protein kinase (AMPK), fibroblast growth factor 10 (FGF10), and adipose triglyceride lipase (ATGL) protein levels both in vivo and in vitro and suppressed lipid metabolism-related genes. Furthermore, the overexpression of FGF10 increased the protein level of AMPK and decreased lipid accumulation in HepG2 cells.

Conclusion: Taken together, the data strongly suggest that betaine significantly prevents high-fat diet-induced NAFLD through the FGF10/AMPK signaling pathway in ApoE mice.
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http://dx.doi.org/10.1007/s00394-020-02362-6DOI Listing
April 2021

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 08 3;3(8):e2012534. Epub 2020 Aug 3.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Importance: Sex, age, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) may affect immune response. However, the association of these factors with the survival benefit of cancer immunotherapy with immune checkpoint inhibitors (ICIs) remains unclear.

Objective: To assess the potential sex, age, and ECOG PS differences of immunotherapy survival benefit in patients with advanced cancer.

Data Sources: PubMed, Web of Science, Embase, and Scopus were searched from inception to August 31, 2019.

Study Selection: Published randomized clinical trials comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs non-ICI control therapy were included.

Data Extraction And Synthesis: Pooled OS hazard ratio (HR) and 95% CI for patients of different sex, age (<65 and ≥65 years) or ECOG PS (0 and ≥1) were calculated separately using a random-effects model, and the heterogeneity between paired estimates was assessed using an interaction test by pooling study-specific interaction HRs. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

Main Outcomes And Measures: The difference in survival benefit of ICIs between sex, age (<65 vs ≥65 years), and ECOG PS (0 vs ≥1), as well as the difference stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Results: Thirty-seven phase 2 or 3 randomized clinical trials involving 23 760 patients were included. An OS benefit of immunotherapy was found for both men (HR, 0.75; 95% CI, 0.71-0.81) and women (HR, 0.79; 95% CI, 0.72-0.88); for both younger (<65 years: HR, 0.77; 95% CI, 0.71-0.83) and older (≥65 years: HR, 0.78; 95% CI, 0.72-0.84) patients; and for both patients with ECOG PS 0 (HR, 0.81; 95% CI, 0.73-0.90) and PS greater than or equal to 1 (HR, 0.79; 95% CI, 0.74-0.84). No significant difference of relative benefit from immunotherapy over control therapy was found in patients of different sex (P = .25, I2 = 19.02%), age (P = .94, I2 = 15.57%), or ECOG PS (P = .74, I2 = 0%). No significant difference was found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Conclusions And Relevance: This meta-analysis found no evidence of an association of sex, age (<65 vs ≥65 years), or ECOG PS (0 vs ≥1) with cancer immunotherapy survival benefit. This finding suggests that the use of ICIs in advanced cancer should not be restricted to certain patients in sex, age, or ECOG PS categories.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414387PMC
August 2020

Pre- and post-irradiation mild hyperthermia enabled by NIR-II for sensitizing radiotherapy.

Biomaterials 2020 10 14;257:120235. Epub 2020 Jul 14.

Intelligent Nanomedicine Institute, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. Electronic address:

The clinical application of cancer radiotherapy is critically impeded by hypoxia-induced radioresistance, insufficient DNA damage, and multiple DNA repair mechanisms. Herein we demonstrate a dual-hyperthermia strategy to potentiate radiotherapy by relieving tumor hypoxia and preventing irradiation-induced DNA damage repair. The tumor hyperthermia temperature was well-controlled by a near infrared laser with minimal side effects using PEGylated nanobipyramids (PNBys) as the photo-transducer. PNBys have narrow longitudinal localized surface plasmon resonance peak in NIR-II window with a high extinction coefficient (2.0 × 10 M cm) and an excellent photothermal conversion efficiency (44.2%). PNBys-induced mild hyperthermia (MHt) prior to radiotherapy enables vessel dilation, blood perfusion, and hypoxia relief, resulting in an increased susceptibility of tumor cells response to radiotherapy. On the other hand, MHt after radiotherapy inhibits the repair of DNA damage generated by irradiation. The PNBys exert hierarchically superior antitumor effects by the combination of MHt pre- and post-radiotherapy in murine mammary tumor EMT-6 model. Consequently, different from the simple combination of RT and MHt, the coupling of pre- and post-MHt with RT by PNBys open intriguing avenues towards new promising antitumor efficacy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120235DOI Listing
October 2020

Richter transformation of chronic lymphocytic leukemia in the era of novel agents.

Authors:
Yucai Wang Wei Ding

Clin Adv Hematol Oncol 2020 Jun;18(6):348-357

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

The increased use of several effective novel targeted therapy agents has revolutionized therapy for patients with chronic lymphocytic leukemia (CLL). Disease progression in patients with CLL continues to occur, however. In particular, 3% to 25% of patients treated with a novel agent develop Richter transformation (RT); that is, histologic transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT that develops in the novel agent era is frequently associated with adverse molecular alterations, such as TP53 disruption and complex karyotype. As a result, patients with RT in the era of novel agents typically have poor responses to the traditional chemotherapy used to treat de novo DLBCL. These patients also tend to have poor survival outcomes, with a median overall survival of less than 1 year. In this article, we review the contemporary literature of RT, particularly in the context of novel agents used for CLL, and discuss the management approach of RT in the novel agent era.
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June 2020

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis.

Blood Adv 2020 07;4(13):2927-2938

Department of Lymphoma and Myeloma and.

Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. We then conducted a meta-analysis using a Bayesian multiregression model to analyze patient-level data in 2127 MCL patients, including prevalence of mutations. In tumor or bone marrow samples taken at diagnosis or baseline, ATM was the most frequently mutated gene (43.5%) followed by TP53 (26.8%), CDKN2A (23.9%), and CCND1 (20.2%). Aberrations were also detected in IGH (38.4%) and MYC (20.8%), primarily through cytogenetic methods. Other common baseline mutations were NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%). Our data also show a change in mutational status from baseline samples to samples at disease progression and present mutations of interest in MCL that should be considered for future analysis. The genes with the highest mutational frequency difference (>5%) are TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1. These findings provide a summary of the mutational landscape of MCL. The genes with the highest change in mutation frequency should be included in targeted next-generation sequencing panels for future studies. These findings also highlight the need for analysis of serial samples in MCL. Patient-level data of prevalent mutations in MCL provide additional evidence emphasizing molecular variability in advancing precision medicine initiatives in MCL.
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http://dx.doi.org/10.1182/bloodadvances.2019001350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362354PMC
July 2020

Self-Reporting and Splitting Nanopomegranates Potentiate Deep Tissue Cancer Radiotherapy Elevated Diffusion and Transcytosis.

ACS Nano 2020 07 7;14(7):8459-8472. Epub 2020 Jul 7.

Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

The efficacy of nanoradiosensitizers in cancer therapy has been primarily impeded by their limited accessibility to radioresistant cancer cells residing deep inside tumor tissues. The failure to report tumor response to radiotherapy generally delays adjustment of the treatment schedule and sets up another substantial obstacle to clinical success. Here, we develop a nanopomegranate (RNP) platform that not only visualizes the cancer radiosensitivities but also potentiates deep tissue cancer radiotherapy via elevated passive diffusion and active transcytosis. The RNPs are engineered through the programmed self-assembly of a tumor environment-targeting polymeric matrix and modular building blocks of ultrasmall gold nanoparticles (Au). Once RNPs reach the tumors, the environmental acidity triggers the splitting and surface cationization of Au. The small dimension of Au allows its passive diffusion, while positive surface charge enables its active transcytosis to cross the tumor interstitium. Meanwhile, the reporter element monitors the feedback of favorable radiotherapy responsiveness by detecting the activated apoptosis after radiation. The pivotal role of RNPs in improving and identifying radiotherapeutic outcomes is demonstrated in various tumor bearing mouse models with different radiosensitivities. In summary, our strategy offers a promising paradigm for deep tissue drug delivery as well as individualized precision radiotherapy.
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http://dx.doi.org/10.1021/acsnano.0c02674DOI Listing
July 2020

Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes.

Ann Hematol 2021 Jan 1;100(1):143-155. Epub 2020 Jun 1.

Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.

Methods: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.

Results: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.

Conclusions: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.
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http://dx.doi.org/10.1007/s00277-020-04094-3DOI Listing
January 2021

Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice.

Leuk Lymphoma 2020 10 25;61(10):2383-2388. Epub 2020 May 25.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.
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http://dx.doi.org/10.1080/10428194.2020.1768384DOI Listing
October 2020

Direct carbonization of organic solvents toward graphene quantum dots.

Nanoscale 2020 May;12(20):10956-10963

High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China. and The Anhui Key Laboratory of Condensed Matter Physics at Extreme Conditions, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China and Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China.

The bottom-up synthesis of graphene quantum dots (GQDs) using solvothermal methods has attracted considerable attention because of their fewer defects and controllable size/morphology. However, the influence of organic solvents on the preparation of GQDs is still unknown. Herein, a systematic study on the carbonization of organic solvents toward GQDs is reported. The results show that organic solvents with the double bond or benzene ring or double hydrophilic groups could be directly decomposed into GQDs without the addition of catalysts or molecular precursors. The as-synthesized GQDs demonstrate ultra-small size distribution, high stability, tunable excitation wavelength and upconverted fluorescence. Both hematological and histopathological analyses show that the as-synthesized GQDs demonstrate a very good safety profile and excellent biocompatibility. The versatility of this synthesis strategy offers easy control of the surface group, composition, and optical properties of GQDs at the molecular level.
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http://dx.doi.org/10.1039/d0nr01903hDOI Listing
May 2020

Bacterial outer membrane vesicles as a platform for biomedical applications: An update.

J Control Release 2020 07 22;323:253-268. Epub 2020 Apr 22.

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address:

Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria both in vitro and in vivo. OMVs are nano-sized spherical vehicles formed by lipid bilayer membranes and contain multiple parent bacteria-derived components. Based on the presence of bacterial antigens, pathogen-associated molecular patterns (PAMPs), adhesins, various proteins and the vesicle structure, OMVs have been developed for biomedical applications as bacterial vaccines, adjuvants, cancer immunotherapy agents, drug delivery vehicles, and anti-bacteria adhesion agents. In this review, we analyze the contributions of the structure and composition of OMVs to their applications, summarize the methods used to isolate and characterize OMVs, and highlight recent progress and future perspectives of OMVs in biomedical applications.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.031DOI Listing
July 2020

Bortezomib-based consolidation or maintenance therapy for multiple myeloma: a meta-analysis.

Blood Cancer J 2020 03 6;10(3):33. Epub 2020 Mar 6.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Bortezomib-based regimens are widely used as induction therapy for multiple myeloma (MM). Unlike lenalidomide, the role of bortezomib in consolidation and maintenance therapy for MM is less clear. We performed a meta-analysis to evaluate the impact of bortezomib-based consolidation and maintenance therapy on survival outcomes and adverse events. PubMed, Web of Science, Embase databases, and major conference proceedings were searched for randomized controlled trials (RCTs) of bortezomib-based regimens as consolidation or maintenance therapy for MM. Ten RCTs enrolling 3147 patients were included in the meta-analysis. Bortezomib-based regimens were compared with regimens without bortezomib or observation. The meta-analysis suggested that bortezomib-based maintenance therapy improved progression-free survival (PFS; hazard ratio [HR] = 0.72, 95% CI 0.55-0.95, P = 0.02) and overall survival (OS; HR = 0.71, 95% CI 0.58-0.87, P = 0.001). Bortezomib-based consolidation therapy improved PFS (HR = 0.77, 95% CI 0.68-0.88, P < 0.001) but not OS (HR = 0.98, 95% CI 0.78-1.24, P = 0.87). Bortezomib-based consolidation/maintenance therapy led to a trend toward increased risk of grade ≥ 3 neurologic symptoms, gastrointestinal symptoms, and fatigue. More research is warranted to further assess the role of bortezomib-based consolidation and maintenance therapy for multiple myeloma.
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http://dx.doi.org/10.1038/s41408-020-0298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060191PMC
March 2020