Effects of miR-373 Inhibition on Glioblastoma Growth by Reducing Limk1 In Vitro

Glioblastoma (GBM) is an aggressive brain tumor with shorter median overall survival time. It is urgent to find novel methods to enhance the therapeutic efficiency clinically. miR-373 is related to the biological development process of cancers, but there are no reports whether modulation on miR-373 could affect GBM development or modify the efficiency of chemo- or radiotherapy yet. Our current study found that the higher level of miR-373 was observed in U-251 cells. Inhibition on miR-373 could reduce the U-251 cell number by 65% and PCNA expression obviously. In addition, inhibition on miR-373 sensitized U-251 cells to chemo- or radiotherapy. The cell cycle of U-251 cells could be modulated by miR-373 knockdown, which could enhance the p21 expression and reduce the cdc2 level. Anti-miR-373 could increase the Bax/Bcl-2 ratio of U-251 cells and induce cell apoptosis significantly. These above effects of miR-373 could be reversed by Limk1 overexpression. Thus, our experimental data confirmed the fact that miR-373 could be a new therapeutic target to enhance the efficiency of chemo- or radiotherapy for clinical GBM patients.

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Caspase 3 Expression in Mantle Cell Lymphoma: An Immunohistochemical Study of 84 Patients.

Blood ◽

10.1182/blood.v106.11.4676.4676 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4676-4676

Author(s):

Carsten Schrader ◽

Wolfram Klapper ◽

Paul Riis ◽

Peter Meusers ◽

Guenter Brittinger ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Survival Time ◽

Median Overall Survival ◽

Caspase 3 ◽

Clinical Course ◽

Cell Lymphoma ◽

Overall Survival Time ◽

Mantle Cell ◽

Median Overall Survival Time

Abstract Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. We investigated immunohistochemically the expression of the apoptotic marker caspase 3 in relation to the clinical course. Biopsy specimen from 84 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, Caspase3. The Caspase3 expression was analyzed in three groups: less than 1 positive cell per high power field (HPF), more than 1 positive cell per HPF and more than 2 positive cells per HPF. The expression was compared with the overall survival data analysed according to Kaplan and Meier. In 75 cases the caspase 3 staining could be analyzed. The caspase 3 expression had a range of 0.1–4.7 positive cells per HPF (median value:1.1, mean:1.3). Patients with mantle cell lymphoma that had less than 1 caspase 3 positive cell per HPF (33 cases) had a median overall survival time of 48 months compared to 27 months for patients with more than 1 positive cell per HPF (24 cases) and 15 months for more than 2 positive cells per HPF (18). The Kaplan-Meier analysis showed a significant difference in the overall survival time between these groups (p<0.0001). The immunohistochemical detection of caspase 3 in mantle cell lymphoma is a predictor for survival in MCL.

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Apoptosis Regulating Proteins bax and p53 in Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v106.11.4710.4710 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4710-4710

Author(s):

Carsten Schrader ◽

Wolfram Klapper ◽

Dirk Janssen ◽

Paul Riis ◽

Peter Meusers ◽

...

Keyword(s):

Overall Survival ◽

Clinical Outcome ◽

Mantle Cell Lymphoma ◽

Survival Time ◽

Median Overall Survival ◽

Cell Lymphoma ◽

P53 Expression ◽

Overall Survival Time ◽

Mantle Cell ◽

Median Overall Survival Time

Abstract In malignant tumors beside cell proliferation also cell death plays role for cell survival. Apoptosis regulating genes can be divided into two groups: death antagonists and death agonists such as bax. The ratio of death agonists and antagonists determines if a cell goes into apoptosis. We investigated in a large collective the immunohistochemical expression of the apoptotic marker p53 and bax in relation to the clinical course. Biopsies were stained immunohistochemically with monoclonal antibodies against bax and p53 and the expression was subdivided in three groups: negative, weak positive and strong positive. The expression profiles were analyzed with the overall survival data according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative p53 expression had a median overall survival time of 38.1 months compared to 22.3 months for patients with a weak and 11.3 months for a strong p53 expression (0<0.0001). The bax expression was in the majority of cases positive. Only one case showed a negative staining. Patients with weak and strong bax expression showed no differences in clinical outcome (median overall survival time: 23 vs 33 months, p=0.6051). The immunohistochemical detection of p53 in mantle cell lymphoma is a good predictor for the clinical outcome.

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Loss of Therapy-Induced Senescence in Myc-Driven Lymphomas Compromises Treatment Outcome In Vivo.

Blood ◽

10.1182/blood.v114.22.1686.1686 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1686-1686

Author(s):

Jan Dörr ◽

Yong Yu ◽

Christoph Loddenkemper ◽

Ulrich Keller ◽

Andreas Buck ◽

...

Keyword(s):

Cell Cycle ◽

Overall Survival ◽

Treatment Outcome ◽

Energy Consumption ◽

Glucose Metabolism ◽

Fdg Pet ◽

Brdu Incorporation ◽

Ki67 Staining

Abstract Abstract 1686 Poster Board I-712 Introduction Premature senescence, a terminal cell-cycle arrest condition, reflects an acute cellular stress response upon a variety of cellular insults including oncogene activation and chemotherapeutic DNA damage. Therefore, senescence potentially complements apoptosis as a safeguard program and tumor-suppressive mechanism. Although it is frequently observed in the clinic that patients who only achieve disease stabilization or partial remission in response to chemotherapy may experience lasting freedom from progression, no tumor model has shown that therapy-induced senescence (TIS) significantly contributes to treatment outcome. Here, we employ the Eμ-myc mouse lymphoma model with and without intact alleles of the histone H3 lysine 9 (H3K9) methyltransferase Suv39h1 (controlling senescence) and of p53 (mediating both apoptosis and senescence) to demonstrate a critical role for senescence in cancer therapy in vivo. Methods Lymphoma cells (LCs), retrovirally transduced with bcl2 to block apoptosis, were treated with the DNA damaging anticancer agent adriamycin (ADR) in vitro, or were exposed to the alkylating agent cyclophosphamide upon lymphoma formation in normal immunocompetent mice in vivo. TIS was analyzed by senescence-associated β-galactosidase activity (SA-β-gal), Ki67 staining and BrdU incorporation. Tumor formation, therapy and progression in vivo was monitored by whole body fluorescence and luciferase imaging and 18F-fluoro-deoxyglucose (FDG) and 18F-fluoro-deoxythymidine (FLT) positron emission tomography (PET). Time-course analysis of glucose and oxygen consumption rates and NAD(P)/NAD(P)H ratios over time were used to define a senescence energy consumption profile. Progression-free and overall survival was evaluated using the Kaplan-Meier method. Results Bcl2-protected control (i.e. no further defined genetic defects) LCs, but not Suv39h1- or p53-deficient LCs, enter TIS in vivo as evidenced by uniform SA-β-gal reactivity, high frequency of H3K9-trimethylation-positive cells, and loss of Ki67 staining and BrdU incorporation due to a cell-cycle block in the G1-phase. Notably, Suv39h1- lymphomas recapitulate the proliferation rate and sensitivity to drug-induced apoptosis of control lymphomas, but display significantly shorter progression-free and overall survival after chemotherapy in vivo. Despite their stable growth arrest ADR-senescent control;bcl2 lymphomas exhibited higher glucose metabolism and energy consumption in vitro when compared to their untreated counterparts or senescence-refractory, ADR-treated Suv39h1-;bcl2 lymphomas. Accordingly, TIS LCs can be non-invasively detected by a discordant positive FDG- but negative FLT-PET scan. Discussion: The study demonstrates that Suv39h1 acts as an essential mediator of TIS without compromising apoptosis or altering the proliferative capacity of lymphoma cells. Myc-driven lymphomas senesce in response to DNA damaging anticancer therapies, but display high levels of glucose metabolism. Therefore, they can be detected by FDG-PET despite their resting condition, indicating that a positive post-therapy FDG-PET scan in the clinic does not necessarily reflect a growing tumor lesion. In vivo, Bcl2-protected Suv39h1- lymphoma-bearing mice succumb dramatically fast to their disease after chemotherapy reminiscent of p53null lymphoma-bearing mice. Hence, Suv39h1-controlled TIS is a critical component of anticancer drug therapy in vivo and significantly extends progression-free and overall survival of the host. Disclosures No relevant conflicts of interest to declare.

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Impaired Mitotic Progression and Preimplantation Lethality in Mice Lacking OMCG1, a New Evolutionarily Conserved Nuclear Protein

Molecular and Cellular Biology ◽

10.1128/mcb.25.14.6289-6302.2005 ◽

2005 ◽

Vol 25 (14) ◽

pp. 6289-6302 ◽

Cited By ~ 11

Author(s):

Jérôme Artus ◽

Sandrine Vandormael-Pournin ◽

Morten Frödin ◽

Karim Nacerddine ◽

Charles Babinet ◽

...

Keyword(s):

Cell Cycle ◽

Zinc Finger Protein ◽

Cell Number ◽

Cell Cycle Regulators ◽

Mammalian Embryo ◽

Mouse Mutants ◽

M Phase ◽

Development In Vitro ◽

Mitotic Figures

ABSTRACT While highly conserved through evolution, the cell cycle has been extensively modified to adapt to new developmental programs. Recently, analyses of mouse mutants revealed that several important cell cycle regulators are either dispensable for development or have a tissue- or cell-type-specific function, indicating that many aspects of cell cycle regulation during mammalian embryo development remain to be elucidated. Here, we report on the characterization of a new gene, Omcg1, which codes for a nuclear zinc finger protein. Embryos lacking Omcg1 die by the end of preimplantation development. In vitro cultured Omcg1-null blastocysts exhibit a dramatic reduction in the total cell number, a high mitotic index, and the presence of abnormal mitotic figures. Importantly, we found that Omcg1 disruption results in the lengthening of M phase rather than in a mitotic block. We show that the mitotic delay in Omcg1 −/− embryos is associated with neither a dysfunction of the spindle checkpoint nor abnormal global histone modifications. Taken together, these results suggest that Omcg1 is an important regulator of the cell cycle in the preimplantation embryo.

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Thyroid Hormone and Estrogen Promote Endocrine Resistance, Proliferation, Dedifferentiation, and Cancer Stem Cells in Steroid Receptor-Positive Breast Cancers

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2010 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A982-A983

Author(s):

Reema S Wahdan-Alaswad ◽

Ann D Thor

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Overall Survival ◽

Thyroid Hormone ◽

Tumor Growth ◽

Cross Talk ◽

Endocrine Resistance ◽

Oncogenic Signaling

Abstract Background: Breast cancer (BC) and thyroid disease are well-recognized comorbidities. Hyperthyroidism and supraphysiologic thyroid hormone (TH) have been shown to promote BC incidence. We recently reported that thyroid hormone replacement therapy (THRT) was significantly and independently associated with shortened disease-free and overall survival, as well as endocrine resistance only in patients with steroid receptor-positive (SR+) BC (1). TH markedly upregulated estrogen and cell cycle signaling in vivo and in vitro and promoted dedifferentiation to basaloid and pre-stem phenotypes. Metformin (Met) attenuated this shift. Mechanisms of TH-mediated endocrine therapy resistance in ER+ BC are the focus of this report. Design: Two clinical cohorts of early-stage lymph node-negative (LN-) SR+ BC patients (n=820 and n=160) were used to determine the effect of THRT on overall survival using Kaplan-Meier methods. Bi-directional cross-talk between TH and E2 was tested using different BC cell lines, ER+ PDX in vivo models, in vitro methods, and publically available in silico data for modeling. Results: Our results show that E2+TH increases cell proliferation, enhances cell cycle, and hormone-associated oncogenic signaling in SR+/ER+ BC. Given that high expression of THRA is associated with poor prognosis in SR+ BC, knockdown of THRA and ESR1 reduced cell proliferation in ER+ BC cells. ER+ PDX tumors were implanted into NSG mice containing E2 pellet and subsequently treated with TH, Tamoxifen (Tam), Fulvestrant (ICI) or Met. Our data show that TH-mediated endocrine resistance only in the E2+TH+Tam treated tumors (P<0.0001 vs E2+Tam alone). Both ICI and Met provided significant attenuation of tumor growth in vivo. RNAseq analysis of E2+TH+Tam tumors show an increase in pro-oncogenic signaling (Wnt/Fizzled, MMPs, and TCL/LEFT). Our data suggest that the use of Tam did not dampen tumor growth whereas a full ER-antagonist (ICI) or Met attenuated E2-TH mediated cross-talk and tumor growth. Conclusions: These findings suggest that TH+Tam may enhance oncogenic signaling and is associated with a significantly increase in mortality risk in ER+/SR+ BC tumors. Exogenous TH adversely affects SR+ BC and not SR- BC. Understanding the mechanism of cross-talk between TH and E2 allows us to define novel therapeutic strategies that will facilitate rapid clinical application for ER+ BC patients currently taking THRT and anti-estrogen treatments. Reference: (1) Wahdan-Alaswad et. al. Clin Cancer Res October 23 2020 DOI: 10.1158/1078-0432.CCR-20-264.

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Efficacy and Safety of Gemtuzumab-Based Regimens in Patients with CD33-Positive Refractory Leukemia.

Blood ◽

10.1182/blood.v110.11.4358.4358 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4358-4358

Author(s):

Suijing Wu ◽

Xin Du ◽

Wei Lin ◽

Jianyu Weng ◽

Jianjun Zhang ◽

...

Keyword(s):

Stem Cells ◽

Overall Survival ◽

Survival Time ◽

Myeloid Leukemia ◽

Median Overall Survival ◽

Response Rate ◽

Single Agent ◽

Efficacy And Safety ◽

Blast Phase ◽

Median Overall Survival Time

Abstract Patients with relapsed or refractory leukemia have less chances of obtaining remission than patients with newly diagnosed.It is reported that more than 80% of acute myeloid leukemia(AML) patients have myeloid blast cells that express the CD33 surface antigen. This antigen also is present on the leukemic stem cells at least some patients with chronic myeloid leukemia(CML)and acute lymphoblastic leukemia(ALL). It is absent from normal hematopoietic stem cells and nonhematopoietic cells and tissues. Gemtuzumab is a humanized anti-CD33 antibody conjugated to calicheamicin, a potent anti tumor antibiotic derived from a bacterium. It is conditionally approved in the US for treatment of CD33+ AML in first relapse in patients over 60 years[Sievers et al.Journal of Clinical Oncology,2001]. Here we evaluate the efficacy and safety of Gemtuzumab -based regimens. The study population comprise 11 patients with CD33-positive refractory leukemia (determined as CD33-antigen expression in over 50% of leukemic blasts by bone marrow aspirates and immunophenotyping), including two with myeloid blast phase of CML, one with refractory ALL, two relapsed after Auto-stem cell transplantation(Auto-SCT). The median age was 47 years. Four cases who were over 60 years or after Auto-SCT treated with single agent. The other seven cases treated with mylotarg and cytotoxic agents, including mylotarg plus idarubine (MI); Gemtuzumab plus fludarabine, cytarabine, CsA(MFAC); or plus mitoxantrone, Ara-C (MMA).The overall response rate was 54% (6/11), with 36%(4/11) patients obtaining complete remission (CR) and 18% (2/11) achieving CRp.The median overall survival time after treatment was 4.8 months, and the median overall survival time after CR was 8.2 months.Two patients with myeloid blast phase of CML achieved CR with BCR/ABL(−), the survival time after CR was 5+months and 20+months respectively, but failed in second relapse. One patient received Allo-SCT after CR with refractory ALL is still alive at present (21months) with disease free. The median time to ANC recovery of 0.5×109/L was 15 days.The common adverse events was myelosuppression (100% Grade 4 neutropenia and thrombocytopenia).Significant non-hematologic toxicitics included infection(96%), infusion-related chills and fever (55%).Although hepatic dysfunction and mucositis were observed,they were generally infrequent and not severe(Grade 1–2).Six patients (55%) developed Hepatic veno-occlusive disease(VOD), four of them were either over 60 years old or received Auto-SCT before although they received only single agent mylotarg therapy, but it was transient and no one died from it. In conclusion, patients with CD33-positive refractory leukemia, Gemtuzumab -based regimens have a comparable response rate and offer a more favorable toxicity profile, expecially for the patients with myeloid blast phase of CML. It is also effective for the patient with refractory ALL. In the treatment, we should pay attention to the hepatic condition of ones who are over 60 years old or after stem cell transplantation, attemps to avoid and treat VOD are warranted. Above all, When patients with refractory leukemia got remission, allogenic-SCT should be done as soon as possible

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Using CHFR expression to predict response and survival after first line treatment with carboplatin-paclitaxel in NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10625 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10625-10625

Author(s):

Rathi Narayana Pillai ◽

Seth Aaron Brodie ◽

Ge Li ◽

James Gordon Herman ◽

Malcolm Brock ◽

...

Keyword(s):

Overall Survival ◽

Median Overall Survival ◽

Medical Center ◽

Objective Response ◽

Subsequent Development ◽

Predictive Marker ◽

Staining Intensity ◽

Adverse Outcomes ◽

First Line

10625 Background: The identification of resistance mechanisms for conventional chemotherapy in lung cancer is of fundamental importance not only for personalization of chemotherapy but also for the subsequent development of novel targeted approaches to overcome this resistance. Currently, there is no clinically validated test for the prediction of response to tubulin-targeted agents in NSCLC. Our previous preclinical work identified Checkpoint with Forkhead and Ringfinger domain” (CHFR) as a predictor of taxane cytotoxicity in in vitro models. The current work assessed the translational significance of this finding in a cohort of US veterans treated at a single-institution. Methods: We studied a cohort of patients with advanced NSCLC treated with taxane-containing frontline regimens at the Atlanta VA Medical Center between 2000 and 2009. Archived paraffin-embedded tissue was retrieved and stained for CHFR expression using standard immunohistochemical techniques. Level of protein expression was assessed by light microscopy and scored for intensity of CHFR staining. Intensity of staining was correlated with clinical outcome including objective response and median overall survival using Chi-Square test and Cox proportional models. Results: We analyzed tumor samples from 45 eligible patients with median age 62.6 years, M/F (44/1). In this cohort, high expression of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 54% in patients with CHFR-high vs. only 18% in those with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p=0.02). Median overall survival was strongly correlated with response to first-line therapy (clinical benefit: 9.24 months; PD: 4.7 months; p<0.001) and with CHFR expression status (CHFR low: 10 months; CHFR high: 5.6 months; p =0.01). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.

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Overexpression of DSCR1 prevents proliferation and predicts favorable prognosis in colorectal cancer patients

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02212-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Wen-Xiang Li ◽

Jia-Jia Zheng ◽

Gang Zhao ◽

Chen-Tao LYU ◽

Wei-Qi Lu

Keyword(s):

Cell Cycle ◽

Overall Survival ◽

Tumor Growth ◽

Cox Regression ◽

Survival Analyses ◽

Cox Regression Analysis ◽

Favorable Prognosis ◽

Kaplan Meier

Abstract Objectives Down syndrome critical region 1 (DSCR1) is associated with carcinogenesis and tumor growth in several types of malignancy. However, little is known about the role of DSCR1 in CRC progression. The present study aimed to elucidate the clinicopathological significance, prognostic, and function roles of DSCR1 in CRC. Methods Firstly, we analyzed DSCR1 expression in 58 paired CRC samples and Oncomine database. Then, we analyzed DSCR1 expression in two independent CRC cohorts (test cohort: n = 70; validation cohort: n = 58) and tested its overall survival (OS) by Kaplan-Meier survival analyses. Finally, we overexpressed DSCR1 in two CRC cell lines DLD1 and LoVo and analyzed its effect on cell cycle and senescence. Results DSCR1 expression was significantly decreased in CRC samples and associated with clinicopathologic features of CRC patients, such as tumor size, lymph node metastasis, and TNM stage. CRC patients with low expression of DSCR1 had shorter overall survival (OS). Kaplan-Meier survival analyses showed that the expression of DSCR1 was significant factor for OS in both cohorts. Multiple Cox regression analysis showed that DSCR1 expression was an independent prognostic marker for OS in test cohort. Overexpression of DSCR1 isoform 4 (DSCR1-4) increased p21, p16, p-NFAT1, and p-NFAT2, while decreased CDK2, CDK4, and Cyclin D1 in CRC cells. In addition, overexpression of DSCR1-4 prevented proliferation and colony formation, and induced senescence in vitro. Moreover, overexpression of DSCR1-4 inhibited tumor growth and tumor angiogenesis in vivo. Conclusions Our study found high expression of DSCR1 contributes to favorable prognosis of CRC patients and prevents cell cycle and proliferation of CRC cells, indicating a critical tumor suppressive role in CRC progression.

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Cell cycle commitment of rat muscle satellite cells.

The Journal of Cell Biology ◽

10.1083/jcb.111.1.201 ◽

1990 ◽

Vol 111 (1) ◽

pp. 201-207 ◽

Cited By ~ 75

Author(s):

R Bischoff

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Satellite Cells ◽

Cell Number ◽

Continuous Exposure ◽

Serum Factors ◽

Muscle Extract ◽

Myogenic Stem Cells

Satellite cells of adult muscle are quiescent myogenic stem cells that can be induced to enter the cell cycle by an extract of crushed muscle (Bischoff, R. 1986. Dev. Biol. 115:140-147). Here, evidence is presented that the extract acts transiently to commit cells to enter the cell cycle. Satellite cells associated with both live and killed rat myofibers in culture were briefly exposed to muscle extract and the increase in cell number was determined at 48 h in vitro, before the onset of fusion. An 8-12-h exposure to extract with killed, but not live, myofibers was sufficient to produce maximum proliferation of satellite cells. Continuous exposure for over 40 h was needed to sustain proliferation of satellite cells on live myofibers. The role of serum factors was also studied. Neither serum nor muscle extract alone was able to induce proliferation of satellite cells. In the presence of muscle extract, however, satellite cell proliferation was directly proportional to the concentration of serum in the medium. These results suggest that mitogens released from crushed muscle produce long-lasting effects that commit quiescent satellite cells to divide, whereas serum factors are needed to maintain progression through the cell cycle. Contact with a viable myofiber modulates the response of satellite cells to growth factors.

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A DNA-structured mathematical model of cell-cycle progression in cyclic hypoxia

10.1101/2021.08.09.455605 ◽

2021 ◽

Author(s):

Giulia Laura Celora ◽

Philip K Maini ◽

Helen M Byrne ◽

Ester M Hammond ◽

Samuel B Bader ◽

...

Keyword(s):

Experimental Data ◽

Cell Cycle ◽

Dna Synthesis ◽

S Phase ◽

Low Oxygen ◽

Oxygen Levels ◽

Wide Range ◽

Model Predictions ◽

Periodic Exposure

New experimental data have shown how the periodic exposure of cells to low oxygen levels (i.e., cyclic hypoxia) impacts their progress through the cell-cycle. Cyclic hypoxia has been detected in tumours and linked to poor prognosis and treatment failure. While fluctuating oxygen environments can be reproduced in vitro, the range of oxygen cycles that can be tested is limited. By contrast, mathematical models can be used to predict the response to a wide range of cyclic dynamics. Accordingly, in this paper we develop a mechanistic model of the cell-cycle that can be combined with in vitro experiments, to better understand the link between cyclic hypoxia and cell-cycle dysregulation. A distinguishing feature of our model is the inclusion of impaired DNA synthesis and cell-cycle arrest due to periodic exposure to severely low oxygen levels. Our model decomposes the cell population into four compartments and a time-dependent delay accounts for the variability in the duration of the S phase which increases in severe hypoxia due to reduced rates of DNA synthesis. We calibrate our model against experimental data and show that it recapitulates the observed cell-cycle dynamics. We use the calibrated model to investigate the response of cells to oxygen cycles not yet tested experimentally. When the re-oxygenation phase is sufficiently long, our model predicts that cyclic hypoxia simply slows cell proliferation since cells spend more time in the S phase. On the contrary, cycles with short periods of re-oxygenation are predicted to lead to inhibition of proliferation, with cells arresting from the cell-cycle when they exit the S phase. While model predictions on short time scales (about a day) are fairly accurate (i.e, confidence intervals are small), the predictions become more uncertain over longer periods. Hence, we use our model to inform experimental design that can lead to improved model parameter estimates and validate model predictions.

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