{"id":"02cc99bb-e0a0-4d77-b6c7-4faa385340c2","arxiv_id":"2505.22580","paper_version":1,"verdict":"CONDITIONAL","confidence":"MODERATE","novelty_score":4.0,"correctness_risk":"medium","formal_verification":"none","parameter_count":4,"one_line_summary":"A hybrid PDE-agent model shows that tumor blood vessels shield resistant cells and that early, frequent mutations plus high proliferation reinforce drug resistance, explaining conflicting T790M findings.","lead":"This paper uses a computer model that combines equations for oxygen and drugs with a cell-by-cell simulation of tumor growth and blood vessel formation to study how drug resistance develops in lung cancer. The model suggests that blood vessels near a tumor protect resistant cells, and that earlier, more frequent mutations give tumors a survival advantage.","discovery_kind":"extension","skeptic_critique":{"model":"deepseek-v4-flash","headline":"The central co-dominance and co-emergence claim rests on single stochastic trajectories; no ensemble statistics or parameter sensitivity are reported, so the qualitative conclusion is not yet established.","rationale":"The reader's weakest assumption identifies exactly the gap I find most load-bearing: the absence of sensitivity analysis and ensemble statistics around the stochastic mutation algorithm and calibrated parameters. The paper's strongest claim is qualitative and evolutionary: high proliferation and high resistance traits reinforce each other and ultimately dominate, and this explains conflicting T790M results. The evidence for that claim is the behavior of individual simulated trajectories; because the model includes Brownian motion, random mutation multipliers, random branching, anastomosis, and daughter placement, a single trajectory cannot distinguish a robust model property from stochastic fluctuation. The paper reports no repeated runs, no confidence intervals, and no variation of the hand-calibrated TAF source k, oxygen supply S_o, or TAF production eta, even though Appendix B states these values were chosen to match experimental vascularization time and to produce the desired qualitative behavior. Without such checks, the central claim remains plausible but unverified. I agree with the reader's conditional verdict: the concern does not by itself invalidate the model, but it does mean the paper as submitted does not yet provide the evidence required to support the central claim. A concrete ensemble test and targeted parameter perturbations would settle whether the concern lands. I do not see a stronger internal inconsistency that would justify moving to reject; the numerical-scheme inconsistency noted by the reader is real but secondary to the central biological claim.","tokens_in":18869,"tokens_out":4298,"duration_ms":59155,"concrete_test":"Run at least 20 independent realizations per configuration (mutation rates mu = 1e-1, 1e-2, 1e-3, 1e-4 with p_r = 0.2) using distinct random seeds, keeping all PDE/ABM parameters fixed. For each run, record the time series of the joint trait distribution, specifically the fraction of cells with both proliferation rate and death threshold above their 90th percentiles, and the first time such cells emerge. If the reported co-dominance and simultaneous-emergence pattern is not consistently reproduced across seeds (e.g., it appears in fewer than 19 of 20 runs), the central claim is unsupported. Additionally, rerun the nominal mu = 0.1 case with k = 5 vs 4 and 6, S_o = 3.5 vs 3.25 and 3.75, and eta = 1000 vs 500 and 2000 to test whether the qualitative conclusion is robust to the hand-calibrated parameters.","verdict_should_be":"UNCHANGED","load_bearing_attack":"The central claim that high proliferation and high resistance traits reinforce each other, culminating in dominance and simultaneous emergence of cells with both traits, is supported only by individual simulation runs in Section 3.6 (Figures 7, 9-12). The model is highly stochastic: cell positions follow Brownian motion, mutation multipliers are drawn from U[0.7,1.7], daughter-cell placement and anastomosis choices are random, and branching is Poisson. With no repeated runs, error bars, or ensemble statistics, the observed co-emergence and final co-dominance could be features of one trajectory rather than robust model behavior. The hand-calibrated values k=5, So=3.5, eta=1000 and the ad hoc mutation-multiplier interval are additional unexamined degrees of freedom; if the qualitative pattern depends on them, the claimed 'mutually reinforcing relationship' and the T790M interpretation are not established. This is a load-bearing evidentiary gap, not a contradiction, but it blocks acceptance of the central claim as stated.","agreement_with_reader":"agree"},"referee_report":{"model":"deepseek-v4-flash","summary":"The paper proposes a hybrid PDE–agent-based model of tumour-induced angiogenesis and drug resistance, coupling reaction–diffusion equations for TAF, drug, and oxygen with agent-based tumour and endothelial cells, including stochastic branching, anastomosis, and a consecutive random mutation algorithm. The numerical study reports that pre-existing resistant cells create a perivascular sanctuary that sustains the tumour under continuous low-dose treatment; that spontaneous mutation at higher rates confers a survival advantage; that high proliferation and high resistance traits appear to reinforce each other and lead to dominance of cells carrying both traits; and that these findings explain conflicting experimental observations on the T790M EGFR mutation in NSCLC. The paper also compares continuous versus pulsed drug-delivery strategies.","tokens_in":19104,"tokens_out":7688,"duration_ms":92054,"significance":"If the reported findings are robust, the model would be a valuable in silico platform for studying how angiogenesis and the tumour microenvironment shape both pre-existing and acquired drug resistance, and it could motivate testable hypotheses about perivascular sanctuary sites and the co-selection of proliferation and resistance traits. The model has several strengths: it integrates a well-established angiogenesis framework (Anderson–Chaplain) with stochastic agent dynamics; it calibrates vascularization time to the 14-day experimental benchmark in Section 3.1; it includes a detailed parameter table and a flowchart in Appendix C; and Section 5(iv) explicitly acknowledges a real limitation (vessel-wall permeability). However, the central qualitative claims currently rest on single stochastic trajectories with hand-tuned parameters, and the clinical interpretation is analogical; unless these gaps are closed, the paper can only support a weaker, hypothesis-generation claim.","major_comments":[{"comment":"The central qualitative claim—that high proliferation rate and high resistance are mutually reinforcing and culminate in the simultaneous emergence and final dominance of cells carrying both traits—is supported only by individual simulation runs. The model is heavily stochastic (Brownian motion for cell positions, U[0.7,1.7] mutation multipliers, random daughter-cell placement, Poisson branching, random anastomosis choices), yet no ensemble statistics, confidence intervals, or even the number of repeated runs are reported. Section 3.1 mentions 'extensive simulations (results not shown)' without giving the ensemble size or a summary statistic. Because the four-mutation-rate comparison and the spatial-overlap claims in Figures 7–12 could arise from a single atypical trajectory, the robustness of the central claim is unverified. Please report means and variances over repeated runs, and quantify the spatial and temporal co-occurrence of high-proliferation and high-resistance cells.","section":"Section 3.6 (Figs. 7, 9–12)"},{"comment":"The proposed 'mutually reinforcing relationship' is partly built into the model by construction. Section 2.4 states that mutations occur 'when tumour cells divide,' and Section 3.6(ii) then reasons that higher proliferation rates, at fixed mutation rates, lead to promoted mutation frequencies. Since mutation events are tied to division, a higher proliferation rate necessarily produces more mutation opportunities per unit time; the resulting positive feedback between proliferation and resistance is therefore a consequence of the mutation algorithm rather than an emergent property of the tumour–microenvironment interactions. To support the claim as an emergent finding, the authors should either decouple the per-unit-time mutation rate from the division rate (for example, by allowing division-independent mutational events and repeating the analysis) or explicitly state that the reinforcement is an assumption of the model.","section":"Section 2.4 and Section 3.6(ii)"},{"comment":"Table 1 is missing the reported success/failure outcomes. The text states that check/cross symbols 'indicate the success and failure of treatment,' but the corresponding table entries are blank for all seven strategies and for both pre-existing and spontaneous resistance. As a result, the paper's comparative claim about treatment strategies—and any inference about optimal dosing—is not supported as printed. Please supply the complete table with the outcome of each strategy, and indicate the criterion used to define success (for example, extinction of the tumour within a specified time horizon). Ideally, report outcomes over an ensemble of stochastic runs rather than a single trajectory.","section":"Section 3.7, Table 1"},{"comment":"The claimed explanation of the T790M paradox is analogical rather than mechanistic. The model tracks generic 'proliferation rate' and 'death threshold' traits and contains no EGFR allele, no TKI, and no T790M; the link from the simulated co-dominance of fast-growing, drug-resistant cells to the conflicting clinical observations of T790M growth disadvantage versus advantage is asserted rather than derived. At minimum, the manuscript should change 'explain' to 'is consistent with a generic mechanism and predicts ...' and specify a clinical or experimental prediction that would distinguish the hypothesis. In addition, the parameter-reporting inconsistencies in Appendix B prevent reproduction of the calibration: the text states that eta is adjusted to 10^3 and that Do=0.35 and rho_o=0.57 are used, but Table B.2 lists eta=6.2669e3, Do=0.64, rho_o=34.3881, and the cell-cycle time is described in the text as 8 hours while Table B.2 gives M_age ~ U[0.9,1.1] days with non-dimensional values 9/16–11/16. These values should be reconciled, and a sensitivity analysis over k=5, S_o=3.5, and the mutation multiplier interval U[0.7,1.7] should be reported.","section":"Section 4 and Appendix B"}],"minor_comments":[{"comment":"The text announces random diffusion, chemotaxis, and haptotaxis, but the flux J_n contains only diffusion and chemotaxis; haptotaxis is never defined.","section":"Section 2.1"},{"comment":"The PDE discretization is described inconsistently: Section 2.1 says forward Euler finite differences are used for all PDEs, while Appendix A.2 introduces an ADI scheme and Section 6 says the ADI method was used; Appendix A.1 only details the endothelial-cell equation. Please clarify which scheme was used for each equation.","section":"Section 2.1 / Appendix A / Section 6"},{"comment":"The flowchart refers to updating 'Fibronection' concentrations, but no fibronectin field appears in the model equations; the flowchart should be aligned with the model.","section":"Appendix C"},{"comment":"The mutation intensity mu is called a Poisson intensity per time step, but Section 3.6 cites the biological rate per replication as 10^-6–10^-2 and then uses mu up to 10^-1; the relationship between the per-replication rate and the time-step intensity should be stated, and the use of values above the cited biological range should be justified.","section":"Section 2.4 / Section 3.6"},{"comment":"The term 'optimal' in the Introduction and Section 3.7 is not supported because only seven fixed strategies are compared and no objective function is defined; consider replacing 'optimal' with 'comparative' unless a formal optimization is performed.","section":"Section 3.7"},{"comment":"There is a typo in the Introduction ('formulalted' in the sentence about Pillay et al.) and inconsistent spelling of 'brush border' ('brush board' in Section 3.1); please proofread.","section":"Introduction and Section 3.1"}],"recommendation":"major_revision","confidential_remarks":"The as-printed Table 1 lacks the outcome symbols that the text explicitly says it contains, which suggests the uploaded version may be incomplete; the editor may wish to verify that the submitted PDF displays correctly. For a numerical analysis journal, the absence of convergence, stability, or mesh-independence verification of the coupled PDE–ABM scheme is also a scope concern; the paper would fit better in a computational oncology venue, provided the robustness and sensitivity analyses described in the major comments are added."},"author_rebuttal":null,"desk_editor":{"model":"deepseek-v4-flash","letter":"Colleague,\n\nHere's my read on arXiv:2505.22580. The headline: plausible qualitative model, but the key claims are not yet backed by the evidence as submitted. The model itself is a genuine synthesis of Anderson-Chaplain angiogenesis and Gevertz-style spatial drug resistance, with a consecutive random mutation algorithm that avoids some abrupt-trait-change artifacts. Calibrating the vascularization time to 14 days is a nice touch, and the spatial figures showing vessel-adjacent survival are suggestive. The paper honestly lists limitations and gives a parameter table.\n\nThe soft spots are significant. The central claims about mutual reinforcement between high proliferation and high resistance, and the T790M explanation, rest on single stochastic trajectories. This model is heavily stochastic—Brownian motion, Poisson branching, random mutation multipliers, random anastomosis—so without ensemble statistics, error bars, or sensitivity analysis, the observed co-dominance could be one trajectory's fluke. The hand-calibrated parameters k=5, So=3.5, eta=1000, and the U[0.7,1.7] multiplier interval are unexamined degrees of freedom. The paper itself says it 'confirms' and 'corroborates' ref [22], which tempers novelty. The T790M link is analogical, not mechanistic: the model traits are not EGFR/T790M biology. Also, Table 1 is broken—success/failure symbols are missing—and there's an internal inconsistency: Section 2 says forward Euler finite differences for all PDEs, while Appendix A.2 and the conclusion describe ADI; the haptotaxis term mentioned in Section 2.1 is absent from the equations. And the 'earlier mutations' part of the claim isn't directly tested; only mutation rate is varied, not the timing of a single mutation.\n\nWho is this for? Researchers in computational oncology who want a working hybrid PDE-ABM framework to build on. They should treat the qualitative conclusions as hypotheses, not results. It deserves a serious referee because the model is nontrivial and the clinical question matters, but the revision must add ensemble statistics, sensitivity analysis, and a toned-down T790M interpretation. I would send it to peer review with a major-revision request, not desk reject.","headline":"Plausible hybrid model with suggestive results, but single-run evidence and hand-tuned parameters leave the central claims unestablished.","tokens_in":19584,"tokens_out":3373,"would_cite":false,"duration_ms":36064,"reading_group":"maybe","serious_thinker":"yes","would_accept_peer_review":true},"rs_alignment":null,"lean_confirmation":null,"pith_extraction":{"msc":["92C50","65M06","35Q92"],"pacs":[],"model":"deepseek-v4-flash","headline":"Tumour blood-vessel networks and early mutations jointly drive drug resistance in a hybrid PDE-agent model.","keywords":["drug resistance","angiogenesis","hybrid discrete-continuous model","agent-based model","non-small cell lung cancer","T790M mutation","tumour microenvironment","mutation-selection feedback"],"falsifier":"Run the same agent-based simulation with the mutation rate decoupled from proliferation, for example as a fixed per-cell probability per time step rather than per division, and check whether high proliferation and high resistance still co-dominate; if they do not, the proposed feedback mechanism is not necessary for the result. Alternatively, in spatial data from EGFR-TKI-resistant non-small cell lung cancer, test whether resistant and fast-proliferating clones preferentially colocalise near vessels, since a uniform distribution would contradict the perivascular sanctuary claim.","tokens_in":1826,"feed_emoji":"🩸","tokens_out":6354,"duration_ms":115972,"temperature":0.7,"pith_summary":"The paper argues that angiogenesis, the growth of new blood vessels into a tumour, does more than feed the tumour: it shapes how drug resistance evolves. Using a hybrid model in which reaction-diffusion equations describe oxygen, drug, and tumour-angiogenic-factor fields while agent-based rules track individual tumour and endothelial cells, the authors simulate two resistance scenarios. With pre-existing resistant cells, newly formed vessels create perivascular sanctuaries where oxygen-driven proliferation outweighs drug damage, letting resistant cells persist. With spontaneous mutation, earlier and more frequent mutations give the tumour a larger survival advantage, and a positive feedback loop emerges: faster proliferators mutate more often, and the drug selects the more resistant survivors, so high proliferation and high resistance come to dominate together. The authors claim this loop resolves conflicting experiments on the T790M second-site EGFR mutation in non-small cell lung cancer, one showing a growth disadvantage and the other showing synergistic oncogenic activity.","feed_headline":"Angiogenesis and early mutations jointly drive drug resistance","feed_subtitle":"Simulation shows vessels create resistance sanctuaries and fast proliferation amplifies mutation-driven survival.","key_machinery":"The engine of the argument is a hybrid discrete-continuous (HDC) model: reaction-diffusion PDEs for tumour angiogenic factor, oxygen, and drug concentration are solved on a grid with finite-difference and alternating-direction implicit methods, while tumour cells and endothelial tip cells are agents with rules for movement, branching, anastomosis, proliferation, apoptosis, and mutation. The load-bearing new component is the consecutive random mutation algorithm, in which each mutation multiplies a cell's death threshold, oxygen consumption rate, and proliferation rate by independent random factors drawn from $U[0.7,1.7]$ (bounded to $[0.5x,4x]$), producing gradual, non-directional trait changes. The feedback loop the authors identify is the mechanism that carries the biological conclusion: proliferation rate controls mutation frequency at a fixed mutation rate, and resistance controls survival under drug, so the two traits reinforce each other under selection and eventually yield dominance of cells carrying both.","core_discovery":"In the paper's own terms, the central discovery is that tumour-induced angiogenesis produces a microenvironment that enhances both pre-existing and mutation-induced drug resistance, and that spontaneous resistance is governed by a mutually reinforcing coupling between proliferation rate and resistance. In the pre-existing case, vessels supply oxygen near the tumour, and because oxygen-driven division halves cellular drug damage at each generation while drug damage accumulates linearly, the region around vessels becomes a sanctuary where resistant cells survive low-dose treatment. In the spontaneous case, a consecutive random mutation algorithm lets daughter cells alter death threshold, oxygen consumption, and proliferation rate by random factors; selection under drug pressure then favours cells with both elevated resistance and elevated proliferation, because at fixed mutation rate more divisions mean more mutation opportunities, and the resistant survivors keep proliferating. The paper identifies this feedback as the reason that cells combining high proliferation with high resistance eventually dominate, and it presents the early-time mutation accumulation window as the period when treatment can still succeed.","pith_inferences":["A testable extension would be to make the mutation rate itself a function of local drug concentration and proliferation state rather than a fixed per-division constant, and to ask whether the high-proliferation/high-resistance correlation strengthens or weakens under that rule.","If the feedback loop is general, then any therapy that decouples division from mutation, such as drugs that slow cycling without killing, should suppress the emergence of dual-trait dominance; this could be checked in agent-based models before clinical translation.","The perivascular sanctuary prediction could be tested against spatial transcriptomics or multiplex imaging of EGFR-TKI-resistant lung tumours: resistant and highly proliferative clones should colocalise near vessels, whereas the model would be undermined if they are uniformly distributed."],"forward_implications":["If the perivascular sanctuary mechanism is right, tumour cells nearest to newly formed vessels should be the hardest to eliminate with low-dose continuous therapy, and vessel-rich regions should be the first site of resistance-driven recurrence.","If earlier and more frequent mutations confer greater survival advantage, then delaying resistance by reducing mutation opportunities, for example by cytostatic control of proliferation, should measurably improve treatment outcome rather than merely delaying regrowth.","The model's resolution of the T790M conflict implies that the growth-disadvantage and growth-advantage phenotypes are not contradictory states of the same mutation but different evolutionary outcomes: the resistance mutation alone can slow growth, while co-selected additional alterations produce aggressively proliferating resistant clones.","The optimal-scheduling comparison in the paper implies that pulsed high-dose and continuous low-dose regimens with equal total dose differ in which resistance mechanism they fail against, so treatment choice should depend on whether resistance is pre-existing or mutation-driven."],"supporting_citations":[{"why":"Supplies the hybrid discrete-continuous angiogenesis framework and the endothelial-cell movement, branching, and anastomosis rules the model builds on.","marker":"[15]"},{"why":"Provides the hybrid multiscale tumour-microenvironment approach and the mutation-selection background used for the agent dynamics.","marker":"[19]"},{"why":"Contributes the drug-resistance niche concept and several parameter values (damage clearance rate, death threshold, drug supply) used in the simulations.","marker":"[20]"},{"why":"Prior multiscale model linking gene mutations and angiogenesis to drug resistance whose conclusions about earlier mutations the paper extends.","marker":"[22]"},{"why":"Presents the conflicting T790M growth-disadvantage findings that the paper's spontaneous-mutation results are meant to explain.","marker":"[6]"},{"why":"Experimental evidence that T790M combined with activating EGFR mutations confers synergistic oncogenic activity, which the paper's high-proliferation/high-resistance dominance is claimed to match.","marker":"[26]"},{"why":"Experimental evidence of enhanced catalytic activity for EGFR mutants, supporting the growth-advantage side of the T790M conflict the model reconciles.","marker":"[27]"},{"why":"Calibration target for vascularization time (14 days) used to set the TAF source strength $k=5$.","marker":"[12]"},{"why":"Motivates the linear initial TAF profile and the quasi-steady-state assumption for the TAF field.","marker":"[14]"}],"fun_headline_variants":["Angiogenesis amplifies both pre-existing and acquired drug resistance","Simulation shows blood vessels boost cancer drug resistance","Angiogenesis creates resistance sanctuaries for tumors","Rapid proliferation and vessels jointly drive drug resistance","Feedback between growth and mutation boosts drug resistance"],"cache_read_input_tokens":21760,"weakest_assumption_plain":"The qualitative conclusions, such as the perivascular sanctuary, the earlier-mutation advantage, and the proliferation-resistance feedback, are assumed to survive changes in the hand-set parameters (TAF source $k=5$, oxygen supply $S_o=3.5$, adjusted TAF production $\\eta=1000$) and in the ad hoc $U[0.7,1.7]$ mutation multiplier, but no sensitivity analysis or ensemble statistics are reported to verify this.","fun_headline_variants_meta":{"raw":{"variants":["Angiogenesis amplifies both pre-existing and acquired drug resistance","Simulation shows blood vessels boost cancer drug resistance","Angiogenesis creates resistance sanctuaries for tumors","Rapid proliferation and vessels jointly drive drug resistance","Feedback between growth and mutation boosts drug resistance"]},"model":"deepseek-v4-flash","effort":"low","cost_usd":0.0007,"raw_usage":{"total_tokens":3169,"prompt_tokens":962,"completion_tokens":2207,"prompt_tokens_details":{"cached_tokens":384},"prompt_cache_hit_tokens":384,"prompt_cache_miss_tokens":578,"completion_tokens_details":{"reasoning_tokens":2133}},"tokens_in":578,"tokens_out":2207,"duration_ms":16370,"temperature":1.0,"reasoning_tokens":2133,"cache_read_input_tokens":384,"cache_creation_input_tokens":0},"cache_creation_input_tokens":0},"created_at":"2026-08-07T13:03:32.736046+00:00","model_set":{"reader":"deepseek-v4-flash"},"falsifier":"Run the same agent-based simulation with the mutation rate decoupled from proliferation, for example as a fixed per-cell probability per time step rather than per division, and check whether high proliferation and high resistance still co-dominate; if they do not, the proposed feedback mechanism is not necessary for the result. Alternatively, in spatial data from EGFR-TKI-resistant non-small cell lung cancer, test whether resistant and fast-proliferating clones preferentially colocalise near vessels, since a uniform distribution would contradict the perivascular sanctuary claim.","supporting_citations":[{"cited_title":"Modeling angiogenesis: A discrete to continuum description","cited_arxiv_id":null,"evidence_quote":"Motivates the linear initial TAF profile and the quasi-steady-state assumption for the TAF field."},{"cited_title":"Continuous and discrete mathematical models of tumor-induced angio- genesis","cited_arxiv_id":null,"evidence_quote":"Supplies the hybrid discrete-continuous angiogenesis framework and the endothelial-cell movement, branching, and anastomosis rules the model builds on."},{"cited_title":"A hybrid multiscale model of solid tumour growth and invasion: evolution and the microenvi- ronment","cited_arxiv_id":null,"evidence_quote":"Provides the hybrid multiscale tumour-microenvironment approach and the mutation-selection background used for the agent dynamics."},{"cited_title":"Emergence of anti-cancer drug resistance: exploring the importance of the microenvironmental niche via a spatial model","cited_arxiv_id":null,"evidence_quote":"Contributes the drug-resistance niche concept and several parameter values (damage clearance rate, death threshold, drug supply) used in the simulations."},{"cited_title":"Multiscale modeling of drug resistance in glioblastoma with gene mutations and angiogenesis","cited_arxiv_id":null,"evidence_quote":"Prior multiscale model linking gene mutations and angiogenesis to drug resistance whose conclusions about earlier mutations the paper extends."},{"cited_title":"Optimization of dosing for egfr-mutant non–small cell lung cancer with evolutionary cancer modeling","cited_arxiv_id":null,"evidence_quote":"Presents the conflicting T790M growth-disadvantage findings that the paper's spontaneous-mutation results are meant to explain."},{"cited_title":"Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the t790m drug resistance mutation","cited_arxiv_id":null,"evidence_quote":"Experimental evidence that T790M combined with activating EGFR mutations confers synergistic oncogenic activity, which the paper's high-proliferation/high-resistance dominance is claimed to match."},{"cited_title":"Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib","cited_arxiv_id":null,"evidence_quote":"Experimental evidence of enhanced catalytic activity for EGFR mutants, supporting the growth-advantage side of the T790M conflict the model reconciles."},{"cited_title":"A mathematical model of tumour-induced capillary growth","cited_arxiv_id":null,"evidence_quote":"Calibration target for vascularization time (14 days) used to set the TAF source strength $k=5$."}],"review_version":1}