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REFERENCE & PURPOSESUBJECTSMETHODOLOGIESRESULTSDATAVARIABLESCONCLUSIONCOMMENTSLINKS
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Author(s), Title, JournalYear PublishedPurpose#Subject CharacteristicsSample Design/ProcedureYear Data CollectedControlIntervention
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Vineela Parvathaneni, SnehalK. Shukla, Nishant S. Kulkarni, Vivek Gupta. Development and characterization of inhalable transferrin functionalized amodiaquine nanoparticles - efficacy in non-small cell lung cancer (NSCLC) treatment. Elsevier International Journal of Pharmaceutics.August 2021To identify if nanoparticle drug delivery systems can be used to carry drugs (such as amodiaquine or AQ) into respirale regions in lung cancer tratement (for example NSCLC) to reduce dose and off-target side effects. 1000 dialysis cassettesHigh pressure homogenization (HPH) was the scale-up method that produced reproducible outcomes. In-vitro release studies were conducted to determine drug-release profile of TF-AMQ NPs. 10,000 dialysis cassettes were preconditioned in buffer for 10 min for hydration; 200 µL of Tf-AMQ NP was loaded into cassettes’ membrane. Cassettes were immersed in a beaker with 100 mL of pH 5.5 buffer to simulate the mild acidic condition in the tumor tissues with 1% polysorbate 80 (37 ◦C). At regular time points of 0.5, 1, 2, 4, 6, 8 24 and 48 h, samples were taken while replacing the dissolution medium with fresh pH5.5 buffer. Amount of AQ released was assessed using UPLC Method. Imaging of AMQ NPs and Tf-AMQ NPs was performed using transmission electron microscopy (TEM) for assessing nanoparticles’ morphology using 5 µL of diluted nanoparticle sample.UPLC Method: chromatography method to measure AQ

Synthesis of Transferrin: target specific drug delivery was achieved by using a surface activation method of polymer nanoparticle surface

Calibration Curve for TF: transferrin solutions for nanoparticles were prepared by diluting with water; fluorescence intensity was measured to create calibration curve

Determining TF Conjugation Efficacy: support from esterase enzymes to promote release of Texas Red Transferring in nanoparticles
Synthesis of TF: Nanoparticles are normally chemically conjugated to different ligands for targeting purposes. This approach resulted in significantly lower drug entrapment (~8%), primarily because of the multiple processing steps involving conjugation of Tf with AQ NPs that needed to take place. For retaining maximum drug loading and minimal steps, PLGA polymer was pre-conjugated with Tf. To maintain scalability of nanoparticle formulation, PLGA polymer was conjugated with targeting moiety, transferrin (Tf), instead of traditional postfabrication conjugation of targeting moiety on nanoparticle surface.

Determining Conjugation Efficiency: Approximately 90–95% Tf conjugation efficiency

In-vitro Release Studies: At 4 h, 80.0 ± 17.6% of encapsulated AQ was released from Tf-AMQ NP at pH 5.5. Results determine that the Tf-AMQ NPs when internalized by tumor cells will capably release the drug, thus possibly ensuing superior cytotoxicity. No rate-limitation based on diffusion of AQ through the membrane was observed.

Morphological Analysis: No aggrevation of nanoparticles was observed during TEM analysis; uniform dispersion of nanoparticles in formulation.

Stability: optimal formulation integrity at both 4 ◦C and room temp (25); developed conjugated NPs are effective delivery systems with desired stability.

In-vitro test - Lung Deposition Test: administered via inhalation with reduced exposure to other organs; Following nebulization, formulations are deposited in the lung airways; efficient peripheral lung deposition

Cellular-Uptake Studies: AQ replaced with fluorescent coumarin to envision uptake; higher accumulation in cancer cells; uptake was found to be time-dependent where even CouNPs have been internalized into the cells effectively with increase in incubation period from 3- to 24 h

3D Spheroid Cell Culture Studies: transferrin receptor targeted AQ-loaded NPs with tumors. In case of solid tumors, the monolayered cell cultures do not simulate tumor structure, resistance to drugs due to tumor microenvironment; At the end of study (Day 12 post-treatment), with a single dose (10 µM) given on day 1, spheroids with no drug treatment (control) were found to have a volume of 11.1 ± 1.7 mm3 compared to spheroid volumes of 11.9 ± 1.3 mm3 (AQ), 13.6 ± 1.1 mm3 (AMQ NP), and 1.9 ± 1.3 mm3 (Tf-AMQ NP). A significant decrease in spheroid dimensions (volume) was observed in Tf-AMQ NP treated spheroids on day 12 		A control tube of AMQ NP and esterase enzyme (1:1 ratio) at similar conditionsTF Conjugated nanoparticles of amodiaquine can be effectively produced using HPH method. A promising candidate for repurposing to consider for NSCLC treatment while delivering inhalable transferrin conjugated nanoparticles developed using a scalable HPH process to the target site, thus reducing the dose, side effects. Nanoparticles must have favorable particle size and surface charge to faciltate internalization of drugs
Developed targeted AQ loaded NPs were compared with their counterpart (non-targeted AQ loaded nanoparticles) for anti-cancer efficacy against NSCLC. Several invitro cell culture studies including cytotoxicity studies and 3D-spheroid studies, methods demonstrating the autophagy inhibition and colony formation confirmed the superior efficacy of transferrin conjugated NPs.		Premise involved repurposing drugs into nanocarriers as nanomedicine-based approach for enhanced cancer therapy. Old drugs such as amodiaquien (antimalarial drug) could be engineered into effective cancer therapies. Nanotherapy encapsulated old drugs into nanocarrier system to improve AQ efficacy by enhancing drug accumulation in tumour cells and programming nanocarriers to have transferrin protein targeted (seeing that tumour cells exhibit overexpression of transferrin receptors). AQ can be used to induce apoptosis in-vitro (programmed cell death outside of a living organism) which is a crucial process in tumour progression. The initial Primary Difficulty was found in choosing a scale-up method that enabled the amount of drugs to be changed from the traditional fixed ratio to a larger amount for therapy;https://pubmed.ncbi.nlm.nih.gov/34438008/
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Biagio Ricciuti, Giuseppe Lamberti, Elisa Andrini, Carlo Genova, Andrea De Giglio, Vanessa Bianconi, Amirhossein Sahebkar, Rita Chiari, Matteo Pirro. Antibody–drug conjugates for lung cancer in the era of
personalized oncology. ELSEVIER.		2021To analyze the biological rational, efficacy and safety of anti-body drug conjugates (ADCs) as therapeutic agents against non-small cell lung cancer and small cell lung cancer. More specifically ADCs that are currently being investigated as therapeutic agents against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).Operate by different mechanisms including induction of apoptosis, antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDCC). Upon binding with their target antigens, ADCs are internalized in clathrin-coated endosome. Later, DC-containing endosomes merge with lysosomes holding several proteases to degrade ADCs and release cytotoxic payloads into the target cells. Payloads induce cell death. Exact mechanisms of cell death largely depend on the type of payload linked to the mAb. When cancer cells targeted by ADCs die, payloads become available to kill other cells within the tumor microenvironment.

Induction of apoptosis: occurs when the tumor-associated antigens are kinase receptors or other molecules actively involved in signal transduction

The molecular profiling of NSCLC has recently allowed for the identification of subsets of patients harboring specific genetic mutations, including epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements. Patients with NSCLC and harboring these actionable genetic alterations can be treated with tyrosine kinase inhibitors (TKIs).		Nanotherapeutic developments in cancer medicine have led to antibody-drug conjugates (ADCs) which are engineered anticancer drugs consisting of recombinant monoclonal antibodies (mAbs) covalently bound to cytotoxic compounds (defined as “payloads”) and directed against tumor-associated antigens. They target tumor cells expressing specific targets and offer a novel therapeutic tool for the management of patients with advanced thoracic malignancies. Self-targeting nanoscale carriers that overcome the limitations of traditional synthetic nanodrugs such as lack of delivery to target cells, low cellular internalization and high clearance.

Preclinical data and phase I/II clinical trials have shown encouraging ACDC results, despite not being formally approved for treatment. However, several issues still lie ahead.
- The expression of ADC targets on the cell surface is theoretically necessary for these drugs to exert their activity. However, in clinical setting the identification of ADC targets in lung cancer is challenging. Tumors are heterogeneous and small specimens; observation of one area might not be representative of the entire tumor, possibly leading to underestimation or overestimation of the presence of ADC targets.

- Does a higher target expression predict a better response to specific ADCs in cancers testing positive for a particular target? Clinical trials show that the response to ADCs may also occur in cancers lacking surface expression of their targets, questioning the specificity of these drugs.		Limitations:

1. Safety Profile:
- Several clinical trials of ADCs have shown unexpected dose-limiting toxicities; possibility that part of the payload is lost in the bloodstream or eventually leaked out from the target cells. Expression pattern of target antigens in healthy tissues is still poorly understood.

2. Acquired resistance
- eventually occurs in most cases. Secondary mutations in genes coding for the target antigens and lysosome pathways, or target
antigens? 		- powerful therapeutic tools for lung cancer. Several ADCs have been investigated in
early-phase clinical trials with promising results and additional research
efforts are ongoing, aimed at identifying novel target antigens and
evaluating both rationally-designed ADCs and new combinations with
other anticancer drugs. In particular, some clinical trials are currently
investigating ADCs in combination with immune checkpoint inhibitors,
on the basis of preclinical evidence showing that ADCs may enhance
immune cell infiltration within the tumor and elicit strong antitumor
responses		https://pubmed.ncbi.nlm.nih.gov/31899248/
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Fan Leng ID , Fang Liu, Yongtao Yang ID , Yu Wu and Weiqun Tian. Strategies on Nanodiagnostics and Nanotherapies of
the Three Common Cancers. MDPI.		2018To examine the recent development and application of nanoparticles in the early diagnosis and treatment of the three common cancers (lung cancer, liver cancer, and breast cancer) by using quantum dots, magnetic nanoparticles, and gold nanoparticles.

https://mdpi-res.com/nanomaterials/nanomaterials-08-00202/article_deploy/nanomaterials-08-00202-v4.pdf
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American Journel of cancer research
Published online 2016 May 1st. Am J Cancer Res. 2016; 6(5): 1118–1134.
Nanoparticle-based targeted gene therapy for lung cancer
Hung-Yen Lee,1 Kamal A Mohammed,1,2 and Najmunnisa Nasreen1,2 		1st May 2016To explore targeted gene therapy with nanoparticles and to look at the major goal of targeted gene therapy, bringing forward a safe and efficient treatment to cancer patients via specifically targeting and deterring cancer cells in the body.Gene therapy involves using oligonucleotides to specifically target and regulate the abnormal genetic expressions which are related to cancer development in cancer cells. Compared to the conventional therapeutic approaches, gene therapy is generally expected to provide higher efficiency on cancer treatments and minimize the systematic cytotoxicity in cancer patients. Most strategies proposed for lung cancer gene therapy requires in vivo gene delivery. In most of the cases, due to their negative charge, the gene molecules such as DNA and RNA biopolymers lack the ability to penetrate the cell membrane and effectively enter into the nucleus. Thus various kinds of vectors and vehicles have been developed to deliver the genetic materials into target cells which showed limited success. With the progression of nanotechnology, nanoparticles composed of various materials have been widely applied in the field of gene delivery for lung cancer treatment. The nanoparticles not only provide protection to the encapsulated nucleotides but also improve the uptake by target cells. In the past decades, nanoparticles with different properties and functionalities have been designed and developed to efficiently deliver therapeutic gene molecules into the target cells directly or via the circulatory system.Invloving exploration in gene delivery and various carriers that had been developed to provide protection to the genetic materials and efficient delivery to targeted cancer cells. Use of different types of nanoparticles: 1.Cationic polymer complexes
2.Polymeric micelles
3.Dendrimers
4.Solid polymeric nanoparticles
5.Liposomes
6.Solid lipid nanoparticles
7.Metal-based nanoparticle systems
2016Nanoparticles based on different materials and functions have been developed and applied in the therapeutic treatment of lung cancers in the last two decades. The utilization of polymer, lipid or metal-based nanoparticle systems in the field of targeted gene delivery has grew tremendously and showed promising in-vitro or in-vivo experimental results in therapeutic efficacy. In the treatment of lung cancers, nanoparticles carrying gene molecules showed high transfection efficiency and targeting ability on lung cancer tumors through systematic or localized administrations. In addition, therapeutic efficiency of gene therapy can be improved by active targeting on specific lung cancer tumors or metastases through modification or conjugation of targeting agents on the surface of the nanoparticles. However, translating these novel nanoparticle-mediated gene delivery techniques into clinical practice is a huge challenge. The challenges of applying nanoparticle-mediated gene delivery within the body, such as maintaining the stability of nanoparticles and gene molecules during delivery, controlling the bio-distribution and pharmacokinetics, penetrating biological barriers and minimizing the potential cytotoxicity of the nanoparticles, need to be considered and overcome before entering into clinical trials. To expand the application of nanoparticle systems in gene therapy in clinics, standards in the examination of nanoparticle safety and evaluation of therapeutic efficacy should be established to guide the direction of research and intervention in gene therapy using nanoparticles. In addition, nanoparticle-based targeted gene delivery can be more widely applied in MPM treatment for improved therapeutics.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889725/#b40
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Ali Aghebati-Maleki, Sanam Dolati, Majid Ahmadi, Amir Baghbanzhadeh, Milad Asadi1, Ali Fotouhi, Mehdi Yousefi, Leili Aghebati-Maleki1. Nanoparticles & Cancer Therapy: Perspectives of Application of Nanoparticles in the Treatment of Cancers. Journal of Cellular Physiology, WILEY.May 29, 2019To examine the general applications of nanotechnology in cancer therapy and discuss the role of NPs in treating cancer among different drug delivery methods for cancer therapy. The effects of altering factors of nanotechnology such as size and material used are also discussed.Nanoparticles (NPs) are used as a targeted therapy technology that manipulates individual atoms and molecules for medical purposes such as cancer identification, drug delivery treatment, and biomedical imaging. The technology allows for personalized cancer therapy treatments by enabling advanced targeting strategies and multifunctionality. Having recently been implemented in the pharmaceutical market, nanotechnology has been used in clinical trials as drug carriers or nanocarriers, in administering nanomedicine agents, and in diagnosing cancer. Primarily considered as nanocarriers, nanotechnology changes the properties that determine how drugs move throughout the body by improving efficacy and decreasing side effects. The carriers act as drug delivery systems (DDS), while simultaneously allowing for the future possibility of imaging to be conducted through methods such as MRIs. By utilizing a wide range of nanomaterials in the construction of DDS, such as organic or inorganic mineral materials, different types of diseases can be targeted. NPs have the potential to target cancerous antigens to trigger appropriate bodily immune responses to target cancerous cells and tissues such as tumours. The applications of nanotechnology are endless for various medical fields with the ability to overcome drug solubility, stability, and resistibility issues while offering more efficient yet less detrimental long-term effects (Aghebati-Maleki et al.).https://onlinelibrary-wiley-com.myaccess.library.utoronto.ca/doi/pdfdirect/10.1002/jcp.29126

https://pubmed.ncbi.nlm.nih.gov/31441032/
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Parvathaneni, Vineela, Mimansa Goyal, Nishant S Kulkarni, Snehal K Shukla, Vivek Gupta. Nanotechnology Based Repositioning of an Anti-Viral Drug for Non-Small Cell Lung Cancer (NSCLC). Pharm Res.


‌		June 8 2020To develop biodegradable (poly (lactic-co-glycolic acid))
PLGA nanoparticles of nelfinavir and determine their efficacy
to treat non-small cell lung cancer (NSCLC).		HIV protease inhibitor, NFV, was
loaded into PLGA nanoparticles by double emulsion/solvent
evaporation method; and nanoparticles were characterized
for physicochemical characteristics including morphology
and intracellular uptake. Their anti-cancer efficacy in
NSCLC was assessed by in vitro assays including cytotoxicity,
cellular migration, colony formation; and 3D spheroid culture
mimicking in-vivo tumor microenvironment. Studies were also conducted to elucidate effects on molecular pathways including apoptosis, autophagy, and endoplasmic stress		 anti-cancer efficacy in
NSCLC was assessed by in vitro assays including cytotoxicity,
cellular migration, colony formation; and 3D spheroid culture
mimicking in-vivo tumor microenvironment. Studies were also conducted to elucidate effects on molecular pathways including apoptosis, autophagy, and endoplasmic stress.		NFV loaded PLGA nanoparticles (NPs) were found to
have particle size: 191.1 ± 10.0 nm, zeta potential: −24.3 ±
0.9 mV, % drug loading: 2.5 ± 0.0%; and entrapment efficiency (EE): 30.1 ± 0.5%. NFV NP inhibited proliferation of
NSCLC cells compared to NFV and exhibited significant
IC50 reduction. From the caspase-dependent apoptosis assays
and western blot studies (upregulation of ATF3), it was revealed
that NFV NP significantly induced ER stress marker ATF3,
cleaved PARP and further caused autophagy inhibition (LC3BII upregulation) leading to increased cellular death. In
addition, NFV NP were found to be more efficacious in penetrating solid tumors in ex-vivo studies compared to plain NFV.		2020Nelfinavir, a lead HIV protease inhibitor can be
repositioned as a NSCLC therapeutic through
nanoparticulate delivery. Given its ability to induce apoptosis
and efficient tumor penetration capability, NFV loaded
PLGA nanoparticulate systems provide a promising delivery
system in NSCLC treatment		https://pubmed.ncbi.nlm.nih.gov/32514688/

https://link-springer-com.myaccess.library.utoronto.ca/content/pdf/10.1007/s11095-020-02848-2.pdf
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Sana Sarkar, Khwaja Osama, Qazi Mohammad Sajid Jamal, Mohammad Amjad Kamal, Usman Sayeed, M Kalim A Khan, Mohd Haris Siddiqui, Salman Akhtar. Advances and Implications in Nanotechnology for Lung Cancer Management. Current Drug Metabolism.2017To Summarizing the advances made in the field of nanotechnology-based lung cancer management.systematically searched for research literature using a well-framed review question and presented data in the tabular forms for readers' convenience.Sixty-four papers were included in the review, the majority of which represent latest researches in the field of nanoparticle-based drug delivery for lung cancer therapy. Conventional treatment strategies for lung cancer lack specificity and are limited by undesirable toxicities in normal cells, as well as a high rate of recurrence. Intervention of nanotechnology has revolutionized the therapy of lung cancer upto a great extent by overcoming the current constraints in conventional therapies. Pulmonary delivery of nano-based drug formulations has resulted in potentially more effective and advanced lung cancer therapy.2017Several nanoscale drug delivery systems for lung cancer treatment are at present in clinical trials and some of them already exist in commercially available forms in the marketplace. However, although nanoscale drug carriers for lung cancer treatment have demonstrated stupendous therapeutic potential at both preclinical and clinical trials, but there are still many limitations to be solved.https://pubmed.ncbi.nlm.nih.gov/27842486/
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Alexander M Cryer, Andrew J Thorley. Nanotechnology in the diagnosis and treatment of lung cancer. Pharmacology & Therapeutics.2019To describe the complexity of lung cancer, the current diagnostic and therapeutic environment, highlight the recent advancements of nanotechnology based approaches in diagnosis and treatment of respiratory malignancies, and provide a brief outlook on the future directions of nanomedicine is providedNanomedicine is now poised to surmount the challenges presented and exert a larger influence on the diagnosis of disease and therapies available in the clinic. Over the coming decades, advances in knowledge and nanotechnological innovations will elevate nanomedicine, specifically NP based drug delivery, from a field of potential to a powerhouse in the transformative treatment of lung cancer and other diseases.https://pubmed.ncbi.nlm.nih.gov/30796927/
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Keshav Raj Paudel, Ridhima Wadhwa, Xin Nee Tew, Natalie Jia Xin Lau, Thiagarajan Madheswaran, Jithendra Panneerselvam, Farrukh Zeeshan, Pradeep Kumar, Gaurav Gupta, Krishnan Anand, Sachin K Singh, Niraj Kumar Jha, Ronan MacLoughlin, Nicole G Hansbro, Gang Liu, Shakti D Shukla, Meenu Mehta, Philip M Hansbro, Dinesh Kumar Chellappan, Kamal Dua. Rutin loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro. Life Sciences.2021To explore the anti-cancer activity of Rutin-loaded liquid crystalline nanoparticles (LCNs) in an in vitro model, evaluate the anti-migratory activity by the scratch wound healing assay and a modified Boyden chamber assay, evaluate the anti-apoptotic activity by Annexin V-FITC staining, and study the colony formation activity using crystal violet stainingRutin-LCNs showed promising anti-proliferative and anti-migratory activities. Furthermore, Rutin-LCNs also induced apoptosis in the A549 cells and inhibited colony formation. The findings warrant further detailed and in-depth anti-cancer mechanistic studies of Rutin-LCNs with a focus towards a potential therapeutic option for NSCLC. LCNs may help to enhance the solubility of Rutin used in the treatment of lung cancer and hence enhance the anticancer effect of Rutin.https://pubmed.ncbi.nlm.nih.gov/33789146/
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American Cancer Society. Getting Oral or Systemic Radiation Therapy.2019To distribute information regarding systemic radiation therapy, and what it ishttps://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/radiation/systemic-radiation-therapy.html#:~:text=Systemic%20radiation%20therapy%20uses%20radioactive,then%20travel%20throughout%20the%20body.
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[Relationship between EGFR and KRAS mutations and prognosis in Chinese patients with non-small cell lung cancer: a mutation analysis with real-time polymerase chain reaction using scorpion amplification refractory mutation system (Article in Chinese) Jie Gao 1, Jia-qi Chen, Li Zhang, Zhi-yong Liang2012To investigate the gene mutation of EGFR and KRAS in Chinese patients with non-small cell lung cancer (NSCLC), and to analyze the relationship between the gene mutations and the clinicopathological features and EGFR-TKI efficiency.EGFR mutation was detected in 120 patients and KRAS mutation in 104 patients with NSCLC in Peking Union Medical College Hospital from March 2009 to December 2010, and the correlation of the gene mutations with the clinicopathological features and EGFR-TKI efficiency was analyzed in the study.EGFR mutation was detected in 44 of 120 (36.7%) patients with NSCLC, in which three types of EGFR gene mutations were found: deletion in exon 19, exon 21 L858R (2573T > G) and Exon 21 L861Q (2582T > A) mutations. There were 29(24.2%) patients with EGFR exon 19 deletion, 14 (11.7%) patients with EGFR exon 21 L858R mutation and one (0.8%) with EGFR exon 21 L861Q mutation in the patients. All the mutations were single point mutations, and no multiple points mutations detected. EGFR mutation rate of bronchioloalveolar carcinoma and adenocarcinoma were higher than that of non-adenocarcinoma (P = 0.009). EGFR mutation rate was higher in female patients or patients without smoking history than male patients or patients with smoking history (P = 0.014, P = 0.001, respectively) in NSCLC patients. EGFR mutation rate was higher in patients without smoking history or patients with well-differentiated carcinoma than patients with smoking history or patients with moderately-and poorly-differentiated carcinoma (P = 0.008, P = 0.018, respectively). There was no difference in prognosis and EGFR-TKI treatment response rate between EGFR mutation patients and EGFR wild-type patients. Nine (8.7%) patients with KRAS mutation were detected in 104 NSCLC patients. There were four types of KRAS gene mutations detected: KRAS Gly12Ala (GGT > GCT), KRAS Gly12Arg (GGT > CGT), KRAS Gly12Val (GGT > GTT) and KRAS Gly12Cys (GGT > TGT). There were 4 patients with Cys mutation, 2 with Arg mutation, 2 with Val mutation and 1 with multiple points mutation of both Cys and Arg in exon 12. No relationship was found between KRAS mutation and clinicopathological feature either in NSCLC or in adenocarcinoma. Prognosis was worse in patients with KRAS mutation than in wild-type patients (P = 0.008). No patient with both EGFR and KRAS mutation was detected.
EGFR mutation rate is related with gender, smoking history and pathological type in NSCLC patients, and is also related with differentiation and smoking history in adenocarcinoma patients. And prognosis is worse in patients with KRAS mutation than that with wild type.https://pubmed.ncbi.nlm.nih.gov/23302304/
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Gene Therapy in Cancer Treatment: Why Go Nano?
Catarina Roma-Rodrigues,1 Lorenzo Rivas-García,1,2 Pedro V. Baptista,1,* and Alexandra R. Fernandes1,*		2020
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