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Pivotal roles of tumor-draining lymph nodes in the abscopal effects from combined immunotherapy and radiotherapy

Cancer Communications 2022年第10期42卷 971-986页

作者： Zhaoyun Liu Zhiyong Yu Dawei Chen vivek verma Chenxi Yuan Minglei Wang Fei Wang Qing Fan Xingwu Wang Yang Li Yuequn Ma Meng Wu Jinming Yu Department of Oncology Shandong University Cancer CenterJinanShandong 250117P.R.China Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong 250117P.R.China Breast Cancer Center Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong 250117P.R.China Department of Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030United States Department of Pharmacy Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong 250117P.R.China Research Unit of Radiation Oncology Chinese Academy of Medical SciencesJinanShandong 250117P.R.China

Background:Currently,due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects,combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1)immune checkpoint inhibition(immuno-radiotherapy,iRT)has revolutionized the therapeutic guidelines.It has been demonstrated that tumor-draining lymph nodes(TDLN)are essential for effective antitumor immunity induced by radiotherapy,immunotherapy,or iRT.Given that the function of TDLN in iRT remains unclear,this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.Methods:The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN.The flow cytometry,multiple immunofluorescence analysis,and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment.Additionally,we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.Results:TDLN deficiency impaired the control of tumor growth by monotherapy.Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects.Furthermore,in the absence of TDLN,the infiltration of CD45+and CD8+T cells was substantially reduced in both primary and abscopal tumors,and the anti-tumor function of CD8+T cells was attenuated as well.Additionally,the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN.RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.Conclusions:TDLN play a critical role in iRT by promoting the infiltration of CD8+T cells and maintaining the M1/M2 macrophage ratio.

关键词： immuno-radiotherapy tumor-draining lymph node T cells tumor-associated macrophage

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A Novel RGL2-DOF6 Complex Contributes to Primary Seed Dormancy in Arabidopsis thaliana by Regulating a GATA Transcription Factor

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Molecular Plant 2017年第10期10卷 1307-1320页

作者： Pratibha Ravindran vivek verma Petra Stamm Prakash P. Kumar Department of Biological Sciences Faculty of Science National University of Singapore Singapore 117543 Singapore present address: Department of Biosciences Durham University South Road Durham DH1 3LE UK

The DELLA protein RGA-LIKE2 （RGL2） is a key transcriptional repressor of gibberellic acid （GA） signaling that regulates seed germination. We identified GATA12, a gene encoding a GATA-type zinc finger transcription factor, as one of the downstream targets of RGL2 in Arabidopsis thaliana. Our data show that freshly harvested （unstratified） seeds of GATA 12 antisense suppression lines have reduced dormancy compared with the wild-type, while ectopic expression lines show enhanced seed dormancy. We show that GATA12 expression is negatively regulated by GA, and its transcript levels decline dramatically under dormancy- breaking conditions such as dry storage and cold stratification of seeds. GATA12 promoter has several GAMYB- and DOF-associated motifs that are known to be GA- and RGL2-responsive, respectively. Chromatin immunoprecipitation assay showed that a protein complex containing RGL2 can bind to GATA12 promoter and thereby regulate its expression. RGL2 lacks a DNA binding domain and requires a transcription factor to induce GATA12 expression. Our data show that this RGL2-containing protein complex includes DNA BINDING1 ZINC FINGER6 （DOF6）, which is a known negative regulator of germination in freshly harvested seeds. We further show that this novel RGL2-DOF6 complex is required for activating GATA12 expression, thus revealing a molecular mechanism to enforce primary seed dormancy.

关键词： seed germination primary dormancy DELLA RGL2 DOF6 gibberellin

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Combined treatment of non-small cell lung cancer using radiotherapy and immunotherapy: challenges and updates

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Cancer Communications 2021年第11期41卷 1086-1099页

作者： Shijie Shang Jie Liu vivek verma Meng Wu James Welsh Jinming Yu Dawei Chen Department of Radiation Oncology Shandong Cancer Hospital Affiliated to Shandong UniversityJinanShandong 250117P.R.China Department of Radiation Oncology Laboratory of Radio-ImmunologyCancer Research CenterShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong 250117P.R.China Department of Radiation Oncology The University of Texas MD Anderson Cancer Center1515 Holcombe BlvdHoustonTexas 77030the United States of America

The efficacy of immunotherapy for advanced non-small cell lung cancer(NSCLC)remains unsatisfactory,as the majority of patients either do not experience an objective response or acquire secondary resistance.As a result,several methods to enhance the systemic efficacy of immunotherapy have been investigated,including a large area of active research by combining immunotherapy with radiation therapy(RT).Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit,we review the progress in this field thus far and explore further avenues for enhancing this combination.This review commences with a discussion of the only two existing randomized trials(and a pooled analysis)showing that the addition of RT to immunotherapy improves the abscopal response rate,progression-free survival,and overall survival in metastatic NSCLC patients.We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT,such as low programmed cell death protein ligand 1(PD-L1)status,tumor mutational burden(TMB),and patient’s immune function.Next,the implementation of RT to overcome immunotherapy resistance is discussed,including a mechanistic discussion and methods with which these mechanisms could be exploited.Lastly,the emerging role of low-dose RT is discussed,which may help to overcome inhibitory signals in the tumor stroma that limit T-cell infiltration.Taken together,given the current state of this rapidly expanding realm,these futuristic strategies may be reflected upon to further enhance the efficacy of immunotherapy for a wider group of patients.

关键词： immune checkpoint inhibitors immunotherapy immunotherapy combined with radiotherapy low-dose radiotherapy non-small cell lung cancer radiotherapy

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Relationship and interactions of curcumin with radiation therapy

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World Journal of Clinical Oncology 2016年第3期7卷 275-283页

作者： vivek verma Department of Radiation Oncology University of Nebraska Medical Center

Curcumin is widely reported to have remarkable medicinal- and antineoplastic- properties. This review details curcumin's relationship with radiotherapy(RT), principally as a radiosensitizer for various malignancies and a radioprotector for normal tissues. First, examples of radiosensitization are provided for various cancers:Pediatric, lymphoma, sarcoma, prostate, gynecologic, pancreas, liver, colorectal, breast, lung, head/neck, and glioma. It is not the purpose of this article to comprehensively review all radiosensitization data; however, high-quality studies are discussed in relationship to currently-controversial RT questions for many cancers, and thus the importance of developing a natural radiosensitizer. Attention is then shifted to radioprotection, for which supporting research is discussed for the following RT toxicities: Dermatitis, pneumonitis, cataractogenesis, neurocognition, myelosuppression, secondary malignancies, and mucositis/enteritis. Though there is fewer data for radioprotection, the overall quality of clinical evidence is higher, and small clinical trials implicating the efficacy of curcumin for RT toxicities(vs placebo/current therapies) are also detailed. Though the overall level of evidence for curcumin as a radiosensitizer and radioprotector is low, it must be recognized that risks of adverse effects are exceedingly low, and clinicians may need to judge the yet-unproven rewards with low toxicity risks.

关键词： Curcumin Turmeric Radiation therapy Cancer Radioprotection Radiosensitization

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Target migration from re-inflation of adjacent atelectasis during lung stereotactic body radiotherapy

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World Journal of Clinical Oncology 2017年第3期8卷 300-304页

作者： Bijing Mao vivek verma Dandan Zheng Xiaofeng Zhu Nathan R Bennion Abhijeet R Bhirud Maria A Poole Weining Zhen Department of Oncology Guizhou Provincial People’s Hospital Department of Radiation Oncology University of Nebraska Medical Center

Stereotactic body radiotherapy(SBRT) is a widely accepted option for the treatment of medically inoperable early-stage non-small cell lung cancer(NSCLC).Herein,we highlight the importance of interfraction image guidance during SBRT.We describe a case of earlystage NSCLC associated with segmental atelectasis that translocated 15 mm anteroinferiorly due to re-expansion of the adjacent segmental atelectasis following the first fraction.The case exemplifies the importance of crosssectional image-guided radiotherapy that shows the intended target,as opposed to aligning based on rigid anatomy alone,especially in cases associated with potentially "volatile" anatomic areas.

关键词： Radiation therapy Stereotactic body radiation therapy Non-small cell lung cancer Image-guided radiation therapy Stereotactic ablative radiation therapy

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非小细胞肺癌放疗联合免疫治疗的研究进展与挑战

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癌症 2023年第11期42卷 571-585页

作者：尚士洁刘洁 vivek verma 吴萌 James Welsh 于金明陈大卫山东大学附属肿瘤医院放疗科山东济南250117 山东第一医科大学附属肿瘤医院放射免疫实验室山东济南250117 Department of Radiation Oncology The University of Texas MD Anderson Cancer Center1515 Holcombe BlvdHoustonTexas 77030the United States of America

由于部分晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者在免疫治疗后没有产生免疫应答或发生继发性耐药,NSCLC免疫治疗的疗效仍不能令人满意。因此,研究者们开展了多项包括放疗(radiation therapy,RT)联合免疫治疗在内的、... 详细信息

由于部分晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者在免疫治疗后没有产生免疫应答或发生继发性耐药,NSCLC免疫治疗的疗效仍不能令人满意。因此,研究者们开展了多项包括放疗(radiation therapy,RT)联合免疫治疗在内的、致力于增强免疫治疗疗效方法的研究。本研究回顾分析了放疗联合免疫治疗提高NSCLC疗效相关研究的进展,并探索进一步增强这一联合治疗疗效的新途径。首先,我们讨论了目前仅有的两项随机试验(和一项汇总分析)。这些试验表明,免疫治疗联合放疗可提高转移性NSCLC患者的远隔客观缓解率、无进展生存期和总生存期。然后,讨论了与放疗免疫疗效相关的因素和生物标志物,例如低水平的程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)、肿瘤突变负荷(tumor mutational burden,TMB)和患者免疫功能。接下来,我们讨论了放疗逆转免疫治疗耐药的机制和应对措施。最后,讨论了低剂量放疗有助于调控肿瘤间质中抑制T细胞浸润的抑制信号的新作用。综上所述,通过对上述研究的深入分析使更多NSCLC患者从免疫治疗中获益。

关键词：免疫检查点抑制剂免疫疗法免疫治疗联合放疗低剂量放疗非小细胞肺癌放疗

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Utility of starchy,lignocellulosics and cellulosics hydrolysates on cellulase production under liquid state fermentation

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Waste Disposal and Sustainable Energy 2019年第4期1卷 289-299页

作者： Nitin verma vivek Kumar M.C.Bansal Department of Paper Technology Indian Institute of TechnologyRoorkee Saharanpur CampusSaharanpurUttar Pradesh 247001India

Starch is one of the most abundant renewable carbohydrate reserves of higher plants.It can be used to produce many valuable food products in the food processing industry.Furthermore,starch is also used as an important feedstock in the fermentation industry to produce value-added products.Lignocellulosic materials such as agriculture and forestry wastes are considered as a renewable feedstock for bioenergy production through a biochemical conversion process.Converting lignocellulosic biomass into fuels and chemicals entail a physicochemical pretreatment of the biomass,followed by enzymatic hydrolysis of the polysaccharide components such as cellulose and hemicellulose into monomeric sugars.These sugars can then be further fermented into other desired compounds of interest.During the deconstruction processes,various inhibitory compounds are released due to the partial over-degradation of lignocellulose biomass,which inhibits the cell growth and metabolic capacity of fermenting strains.Cellulosic materials such as waste paper in large quantities can also be used as potentially cheap feedstock for sustainable production of value-added products.The present investigation is mainly focused on the utility of starchy hydrolysates(wheat,potato,and rice)and lignocellulosics hydrolysates(bagasse and wheat straw)in cellulase production under liquid state fermentation.It also depicts the potential of cellulosic hydrolysate(waste newspaper)in product formation.

关键词： Starch hydrolysate Bagasse hydrolysate Wheat straw hydrolysate Waste newspaper hydrolysate Cellulases

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Levels of neutrophil gelatinase-assosciated lipocalin in patients with head and neck squamous cell carcinoma in Indian population from Haryana state

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World Journal of Clinical Oncology 2017年第3期8卷 261-265页

作者： Monica verma Kiran Dahiya Abhishek Soni Rakesh Dhankhar Veena S Ghalaut Aastha Bansal vivek Kaushal Department of Biochemistry Pt.B.D.SharmaUniversity of Health Sciences Department of Radiotherapy Pt.B.D.SharmaUniversity of Health Sciences

AIM To study the levels of neutrophil gelatinase associated lipocalin(NGAL) in head and neck squamous cell carcinoma(HNSCC).METHODS This was a non randomized case control study conducted at Department of Biochemistry,in collaboration with Regional Cancer Center over a period of one year.The study population included 50 adult newly diagnosed HNSCC patients reporting in outpatient department at Regional Cancer Center and compared with 50 healthy controls.NGAL was estimated by ELISA technique.Student t test and χ~2 test were applied for comparison of means of study groups.Correlations between groups were analyzed using Pearson correlation coefficient(r) formula.RESULTS Patients with HNSCC exhibited significantly increased levels of NGAL(P < 0.05) as compared to healthy controls(978.88 ± 261.39 ng/mL vs 34.83 ± 7.59 ng/mL).Out of 50,26 patients(52%) were in stage Ⅳ,21(42%) in stage Ⅲ,1(2%) patient in stage Ⅱ and 2(4%) patients were in stage Ⅰ.Metastasis was absent in 98% patients and mean NGAL levels were highest in these patients but P value was not significant.Mean NGAL levels were highest in stage Ⅳ [1041.54 ± 222.15 ng/mL(stage Ⅳ) vs 1040 ± 0.00 ng/mL(stage Ⅰ);900 ± 0.00 ng/mL(stage Ⅱ) and 1031.90 ± 202.55 ng/mL(stage Ⅲ)] and χ~2 test was highly significant(P < 0.001).Thirty-six patients(72%) were having moderately differentiated HNSCC and mean NGAL levels were maximum in patients with well differentiated HNSCC(1164 ± 315.64 ng/mL vs 1013.33 ± 161.19 ng/mL in moderately differentiated and 890 ± 11.55 ng/mL in poorly differentiated) and the results were also highly significant(P < 0.001,χ~2 test).CONCLUSION The present work demonstrates a potential role of NGAL as cancer biomarker and its use in monitoring the HNSCC progression.

关键词： Neutrophil gelatinase associated lipocalin Head and neck squamous cell carcinoma Metastasis Biomarker Lipocalin 2

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Autochthonous halotolerant plant growth-promoting rhizobacteria promote bacoside A yield of Bacopa monnieri(L.)Nash and phytoextraction of salt-affected soil

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Pedosphere 2020年第5期30卷 671-683页

作者： Umesh PANKAJ Durgesh Narain SINGH Pooja MISHRA Pooja GAUR C.S.vivek BABU Karuna SHANKER Rajesh Kumar verma Department of Soil Science CSIR-Central Institute of Medicinal and Aromatic PlantsLucknow 226015(India) Division of Biotechnology CSIR-Central Institute of Medicinal and Aromatic PlantsLucknow 226015(India) Division of Microbial Technology CSIR-Central Institute o f Medicinal and Aromatic PlantsLucknow 226015(India) Analytical Chemistry Department CSIR-Central Institute o f Medicinal and Aromatic PlantsLucknow 226015(India) Research Centre CSIR-Central Institute of Medicinal and Aromatic PlantsBangalore 560065(India)

Phytoremediation is a promising approach for reclamation of salt-affected soil.Phytoextraction is the most commonly used process,which exploits plants to absorb,immobilize,and accumulate salt in their shoots.In this study,halotolerant plant growth-promoting rhizobacteria(PGPR)were isolated from the rhizosphere of wild grasses growing naturally in salt-affected areas of Lucknow,Uttar Pradesh(India)and were tested for their efficacies of salt-tolerance and plant growth-promoting(PGP)abilities.Based on 16S rRNA sequences,the most efficient halotolerant isolates possessing PGP traits were identified as Pseudomonas plecoglossicida(KM 233646),Acinetobacter calcoaceticus(KM 233647),Bacillus flexus(KM 233648),and Bacillus safensis(KM 233652).Application of these isolates as bio-inoculants significantly(P<0.05)increased the growth and bacoside A yield of a medicinal plant,Bacopa monnieri(L.)Nash,grown on natural salt-affected soil.The phytoremediation of salt-affected soil was evident by the substantial increase in shoot Na^+:K^+ratio of bio-inoculant-treated plants.When compared to un-inoculated control plants,the soil physico-chemical properties of bio-inoculant-treated plants were improved.The shoot and root biomass(fresh and dry weights),soil enzymes,and soil nutrient parameters showed significant positive correlations with the shoot Na+:K+ratio.Consequently,the halotolerant PGPR screened in this study could be useful for the reclamation of saline soils concomitant with improved plant growth and bacoside A yield.

关键词： bio-inoculant phytoremediation plant productivity soil physico-chemical property soil salinity

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帕博利珠单抗单用或与放疗联用治疗转移性非小细胞肺癌:两个随机试验的汇总分析

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中华肿瘤防治杂志 2021年第24期28卷 1841-1850页

作者：陈大卫(翻译) 于金明(校对) Willemijn S M E Theelen vivek verma Brian P Hobbs Heike M U Peulen Joachim G J V Aerts Idris Bahce Anna Larissa N Niemeijer Joe Y Chang Patricia M de Groot Quynh-Nhu Nguyen Nathan I Comeaux George R Simon Ferdinandos Skoulidis Steven H Lin Kewen He Roshal Patel John Heymach Paul Baas James W Welsh 山东省肿瘤防治研究院(山东省肿瘤医院) 山东第一医科大学(山东省医学科学院)山东济南250117 不详 Department of Radiation Oncology The University of Texas M D Anderson Cancer CenterHoustonTX 77030USA

背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,... 详细信息

背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,联合疗法组显示出潜在获益。由于每个研究的样本量较小,缓解率和结局并未显示出统计学意义,然而却有显著的临床获益。因此,本研究进行汇总分析,来判断放疗是否会改善转移性NSCLC患者的免疫治疗应答。方法PEMBRO-RT和MDACC研究纳入标准:患者年龄≥18岁,患有转移性NSCLC,且有≥1处未经放疗照射的病灶,以便进行射野外应答监测。PEMBRO-RT研究纳入曾接受过化疗患者,MDACC研究纳入曾接受过治疗或新诊断患者。2个研究中的患者均未接受过免疫治疗。在PEMBRO-RT研究中患者被等比例随机分配入组,并根据吸烟状态进行分层(分为<10年组和≥10年组)。MDACC研究的患者根据放疗计划可行性被等比例随机分配入2个受试组。由于联合治疗组的干预本质,每个研究中的放疗均不适用盲法。在2个研究中,不论是否进行放疗,均静脉滴入帕博利珠单抗(每3周200 mg)。在PEMBRO-RT研究中,在放疗(24 Gy 3次分割照射)结束后1周给予第1剂帕博利珠单抗。在MDACC研究中,在第1次放疗(50 Gy 4次分割照射或45 Gy 15次分割照射)同时给予帕博利珠单抗。仅检测未经照射病灶的应答。本研究的终点为最佳射野外(远隔)应答率(ARR)、最佳射野外疾病控制率(ACR)、12周时ARR、12周时ACR、无进展生存期(PFS)和总生存期(OS)。2个研究的意向治疗(ITT)人群均纳入分析。PEMBRO-RT研究(NCT02492568)和MDACC研究(NCT02444741)均在ClinicalTrials.gov上注册。发现纳入148例患者,76例接受帕博利珠单抗治疗,72例接受帕博利珠单抗+放疗治疗。所有患者随访时间中位数为33个月[四分位距(IQR):32.4~33.6]。148例患者中124例(84%)组织学特征为非鳞癌,111例(75%)患者曾经接受过化疗。组间没有基线特征差异,包括PD-L1表达状态和转移灶体积。最常见的照射部位为肺转移灶(39%,28/72)、胸腔内淋巴结(21%,15/72)和非原发灶(17%,12/72)。帕博利珠单抗组和联合治疗组的最佳ARR分别为19.7%(15/76)和41.7%(30/72),OR=2.96,95%CI:1.42~6.20,P=0.0039;最佳ACR分别为43.4%(33/76)和65.3%(47/72),OR=2.51,95%CI:1.28~4.91,P=0.0071;PFS中位数分别为4.4(IQR:2.9~5.9)和9.0个月(IQR:6.8~11.2),HR=0.67,95%CI:0.45~0.99,P=0.045;OS中位数分别为8.7(IQR:6.4~11.0)和19.2个月(IQR:14.6~23.8),OR=0.67,95%CI:0.54~0.84,P=0.0004。在汇总分析中没有发现新的安全问题。解读帕博利珠单抗免疫疗法+放疗显著提高转移性NSCLC患者的应答和改善治疗结局。这些结果需要在三期临床试验中进行验证。

关键词：帕博利珠单抗非小细胞肺癌放疗汇总分析

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