Postoperative rehabilitation and quality of life evaluation for transoral endoscopic thyroidectomy vestibular approach.

There are no targeted rehabilitation training modalities and assessment tools for patients after transoral endoscopic thyroidectomy vestibular approach (TOETVA). Herein, we develop a new assessment questionnaire and rehabilitation training modality and evaluate its safety and effectiveness. The THYCA-QoL-TOETVA questionnaire was compiled, and reliability and validity analyses were performed. Patients were divided into the new rehabilitation training group (N) or the conventional rehabilitation training group (C), and 1:1 propensity score matching (PSM) was performed after administering questionnaires to patients in both groups. Cervical range of motion (CROM) data were also measured and collected for statistical analysis. The questionnaire used in this study showed good expert authority, coordination, internal consistency, and questionnaire reliability. A total of 476 patients were included after PSM, and the questionnaire results showed that recovery and quality of life were better in the N group than in the C group (124.55 ± 8.171 vs. 122.94 ± 8.366, p = 0.026). Analysis of cervical spine mobility showed that rehabilitation was better in the N group compared to the C group at postoperative one month (flexion: 1.762°, extension: 4.720°, left lateral bending: 3.912°, right lateral bending: 4.061°, left axial rotation: 5.180°, right axial rotation: 5.199°, p value all of these < 0.001), and at postoperative three months (flexion: 2.866°, extension: 2.904°, left lateral bending: 3.927°, right lateral bending: 3.330°, left axial rotation: 4.395°, right axial rotation: 3.992°, p value all of these < 0.001). The THYCA-QoL-TOETVA provides an appropriate and effective tool for measuring the postoperative quality of life of TOETVA patients. This new rehabilitation training can effectively alleviate the problem of limited neck movement and improve the quality of life of patients after TOETVA surgery.Trial registration: ChiCTR2300069097.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

Effects of low dose radiation on behavior rhythm of zebrafish (Danio rerio).

Biological rhythm refers to the internal regulation of various life activities of an organism, which are determined by the specific time structure sequences of each individual. Behavior rhythm is the most intuitive embodiment of biological rhythm. To study the effect of low dose radiation on behavioral rhythm, zebrafish (Danio rerio) was used as a model organism in this study. The early embryos of zebrafish were irradiated at doses of 0.01, 0.1, and 1 Gy to observe the changes in zebrafish development, circadian rhythm, key clock genes, related RNA and protein expression, and melatonin. The results revealed that 0.1 and 1 Gy radiation could lead to different degrees of telencephalic nerve cell apoptosis and the formation of vacuolar structures. 0.1 and 1 Gy radiation could reduce the hatching rate of zebrafish embryos at 72 hpf and delay embryo hatching. The analysis of circadian behavior at 120 hpf demonstrated that 1 Gy dose of radiation altered the circadian rhythm of zebrafish, as well as decreased the distance, amplitude, and phase of movement. RT-PCR analysis of the key clock genes (bmal1b, clock1a, per1b, per2, cry2, and nr1d1) involved in regulating circadian rhythm was performed. The results showed that 1 Gy radiation could interfere with the expression of clock genes in zebrafish embryos and upregulate bmal1b, clock1a, and per1b. Western blot experiments further verified the protein expression of key clock genes, bmal1b and clock. Detection of melatonin secretion at different time points over 24 h showed that radiation doses of 0.1 and 1 Gy could increase melatonin secretion. Based on these findings, it is speculated that a certain dose of radiation may affect melatonin secretion, which impacts the telencephalon structure and ontogeny of zebrafish, delays hatching, and changes the circadian rhythm. This effect is thought to be achieved through upregulating the expression of circadian rhythm genes, clock1a and per1b and related proteins, which may be responsible for the abnormal circadian rhythm caused by radiation.

The alteration of the expression level of neuropathy target esterase in human neuroblastoma SK-N-SH cells disrupts cellular phospholipids homeostasis.

Neuropathy target esterase (NTE) has been proven to act as a lysophospholipase (LysoPLA) and phospholipase B (PLB) in mammalian cells. In this study, we took human neuroblastoma SK-N-SH cells as the research object and explored the effect of NTE on phospholipid homeostasis. The results showed that phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) levels significantly increased (> 40%), while glycerophosphocholine (GPC) decreased (below 60%) after NTE gene was knockdown in the cells (NTE < 30% of control), which were prepared by gene silencing with dsRNA-NTE. However, in the NTE-overexpressed cells (NTE > 50% of control), which were prepared by expressing recombinant catalytic domain of NTE, LPC remarkably decreased (below 80%) and GPC enhanced (> 40%). Mipafox, a neuropathic organophosphorus compound (OP), significantly inhibited NTE-LysoPLA and NTE-PLB activities (> 95-99% inhibition at 50 µM), which was accompanied with a decreased GPC level (below 40%) although no change of the PC and LPC levels was observed; while paraoxon, a non-neuropathic OP, suppresses neither the activities of NTE-phospholipases nor the levels of PC, LPC, and GPC. Thus, we concluded that both the stable up- or down-regulated expression of NTE gene and the loss of NTE-LysoPLA/PLB activities disrupts phospholipid homeostasis in the cells although the inhibition of NTE activity only decreased GPC content without altering PC and LPC levels.

Ivermectin inhibits tumor metastasis by regulating the Wnt/ß-catenin/integrin ß1/FAK signaling pathway.

Tumor metastasis is the major cause of cancer mortality; therefore, it is imperative to discover effective therapeutic drugs for anti-metastasis therapy. In the current study, we investigated whether ivermectin (IVM), an FDA-approved antiparasitic drug, could prevent cancer metastasis. Colorectal and breast cancer cell lines and a cancer cell-derived xenograft tumor metastasis model were used to investigate the anti-metastasis effect of IVM. Our results showed that IVM significantly inhibited the motility of cancer cells in vitro and tumor metastasis in vivo. Mechanistically, IVM suppressed the expressions of the migration-related proteins via inhibiting the activation of Wnt/ß-catenin/integrin ß1/FAK and the downstream signaling cascades. Our findings indicated that IVM was capable of suppressing tumor metastasis, which provided the rationale on exploring the potential clinical application of IVM in the prevention and treatment of cancer metastasis.

Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review).

Calcium (Ca2+) is an essential signaling molecule in all cells. It is involved in numerous fundamental functions, including cell life and death. Abnormal regulation of Ca2+ homeostasis may cause human diseases. Usually known as a member of the transient receptor potential (TRP) family, TRP ankyrin 1 (TRPA1) is the only member of the ankyrin subfamily identified in mammals so far and widely expressed in cells and tissues. As it is involved in numerous sensory disorders such as pain and pruritus, TRPA1 is a potential target for the treatment of neuropathy. The functions of TRP family members are closely related to Ca2+. TRPA1 has a high permeability to Ca2+, sodium and potassium ions as a non-selective cation channel and the Ca2+ influx mediated by TRPA1 is involved in a variety of biological processes. In the present review, research on the relationship between the TRPA1 channel and Ca2+ ions and their interaction in disease-associated processes was summarised. The therapeutic potential of the TRPA1 channel is highlighted, which is expected to become a novel direction for the prevention and treatment of health conditions such as cancer and neurodegenerative diseases.

The role of protein kinase C alpha in tri-ortho-cresyl phosphate-induced autophagy in human neuroblastoma SK-N-SH cells.

As an organophosphorus ester, tri-ortho-cresyl phosphate (TOCP) has been widely used in agriculture and industry. It is reported that TOCP can induce organophosphate-induced delayed neuropathy (OPIDN) in sensitive animal and human species. However, the exact molecular mechanisms underlying TOCP-induced neurotoxicity are still unknown. In this study, we found that TOCP could induce autophagy by activating protein kinase C alpha (PKCα) signaling in neuroblastoma SK-N-SH cells. PKCα activators could positively regulate TOCP-induced autophagy by increasing the expression levels of neighbor BRCA1 gene protein 1 (NBR1), LC3 and P62 autophagic receptor protein. Furthermore, PKCα activation impaired the ubiquitin-proteasome system (UPS), resulting in inhibition of proteasome activity and accumulation of ubiquitinated proteins. UPS dysfunction could stimulate autophagy to serve as a compensatory pathway, which contributed to the accumulation of the abnormally hyperphosphorylated tau proteins and degradation of impaired proteins of the MAP 2 and NF-H families in neurodegenerative disorders.

Comparison of Autocross-Linked Hyaluronic Acid Gel and Intrauterine Device for Preventing Intrauterine Adhesions in Infertile Patients: A Randomized Clinical Trial.

OBJECTIVES: The objective of this study is to evaluate the efficacy of autocross-linked hyaluronic acid (HA) compared with intrauterine device (IUD) for preventing intrauterine adhesions (IUAs) in infertile patients after hysteroscopic adhesiolysis. MATERIALS AND METHODS: A randomized clinical trial (ChiCTR-IOR-16007746). Upon completion of adhesiolysis, 3 ml of HA gel was placed into the uterine cavity in Group A; 3 ml of HA gel and an IUD were placed in Group B; and only an IUD was placed in Group C. A second hysteroscopic examination was performed in all patients at approximately 1 month postoperatively for the evaluation of IUA. The primary outcome measure was the effective rate of IUA prevention based on the American Fertility Society (AFS) scoring system. RESULTS: Eighty-nine women were randomly distributed into two groups for intention to treat with 30 patients in Group A, 24 patients in Group B, and 35 patients in Group C. Patients were scored and stratified into three degrees and were enrolled using the simple random sampling method. The three groups were well balanced. There were no significant differences in age, endometrial thickness, the previous number of pregnancy, and the distribution of adhesion categories across mild, moderate, and severe between the three groups. The effective rate of IUA prevention, the AFS score after therapy, and the percentage improvements of Chinese score and AFS score before and after surgery were statistically significant difference between Groups A and C. The clinical pregnancy rate in Group A was higher than those in Groups B and C, but the difference was not statistically significant. CONCLUSION: HA gel has an advantage over an IUD in reducing IUA recurrence and decreasing adhesions.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases.

Ferroptosis is a kind of regulated cell death (RCD) caused by the redox state disorder of intracellular microenvironment controlled by glutathione (GSH) peroxidase 4 (GPX4), which is inhibited by iron chelators and lipophilic antioxidants. In addition to classical regulatory mechanisms, new regulatory factors for ferroptosis have been discovered in recent years, such as the P53 pathway, the activating transcription factor (ATF)3/4 pathway, Beclin 1 (BECN1) pathway, and some non-coding RNA. Ferroptosis is closely related to cancer treatment, neurodegenerative diseases, ischemia-reperfusion of organ, neurotoxicity, and others, in particular, in the field of neurodegenerative diseases treatment has aroused people's interest. The nuclear factor E2 related factor 2 (Nrf2/NFE2L2) has been proved to play a key role in neurodegenerative disease treatment and ferroptosis regulation. Ferroptosis promotes the progression of neurodegenerative diseases, while the expression of Nrf2 and its target genes (Ho-1, Nqo-1, and Trx) has been declined with aging; therefore, there is still insufficient evidence for ferroptosis and Nrf2 regulatory networks in the field of neurodegenerative diseases. In this review, we will provide a brief overview of ferroptosis regulatory mechanisms, as well as an emphasis on the mechanism of Nrf2 regulating ferroptosis. We also highlight the role of ferroptosis and Nrf2 during the process of neurodegenerative diseases and investigate a theoretical basis for further research on the relationship between Nrf2 and ferroptosis in the process of neurodegenerative diseases treatment.

Optimal waiting period for fresh embryo transfer after hysteroscopic adhesiolysis: a retrospective cohort study.

BACKGROUND: Very few studies have been conducted regarding the optimal time interval between hysteroscopic adhesiolysis and the embryo transfer (ET). Investigation of this optimal time may be helpful for assisted reproductive technology. Therefore, we investigated effects of the interval between hysteroscopic adhesiolysis and ET upon in vitro fertilization (IVF) cycle outcomes. METHODS: Patients were recruited between January 2014 and September 2017 at the Reproductive Hospital Affiliated to Shandong University. Patients who were diagnosed with intra-uterine adhesion (IUA) and underwent hysteroscopic adhesiolysis before fresh IVF-ET or intra-cytoplasmic sperm injection cycles were classified into three groups according to the interval between hysteroscopic adhesiolysis and ET: less than 90 days (Group 1), 90 to 180 days (Group 2), and greater than 180 days (Group 3). Baseline characteristics, controlled ovarian stimulation (COS) response, and pregnancy outcomes after ET were compared. Analysis of variance or non-parametric tests were used to test numerical data. The Pearson's Chi-squared test was used to test categorical data. RESULTS: A total of 312 patients were recruited as follows: 112 in Group 1, 137 in Group 2, and 63 in Group 3. There were no differences in baseline and COS characteristics among the three groups. The live-birth rate in Group 2 (40.1%) was significantly higher than that in Group 1 (17.9%; χ = 14.545, P < 0.001). There were no significant differences in the rates of biochemical, ongoing, and clinical pregnancy, and biochemical and clinical pregnancy abortion, as well as stillbirth among the groups. In the mild IUA patients, the live-birth rate was significantly higher in Group 2 (42.6%) compared with Group 1 (22%; χ = 8.413, P = 0.004). In the moderate IUA patients, Group 2 (35.7%) had a higher frequency of live births than Group 1 (6.7%; χ = 8.187, P = 0.004). CONCLUSIONS: The optimal waiting period for fresh ET after hysteroscopic adhesiolysis was 90 to 180 days in the current study.

Medulloblastoma with soft-tissue and skeletal metastases in an adult: A case report.

Medulloblastoma (MB) is a highly malignant primary brain tumor, which occurs in the cerebellum or posterior cranial fossa. MB is most commonly identified in children <10 years of age. The disease is rare in adults, affecting patients aged between 30 and 50 years of age, with an incidence of 0.5 cases per 1,000,000 individuals. Extraneural metastases are reported in 7-10% of cases, most commonly involving the bones and more rarely involving the lymph nodes, visceral organs and bone marrow. The current study presents the case of a 36-year-old male who underwent a gross total resection followed by radiation therapy to the craniospinal axis for the treatment of MB. The patient subsequently developed widespread metastasis, which involved the soft tissue of the occipital bone. Subsequently, the patient was administered palliative radiotherapy and initially exhibited a good clinical response. However, the patient succumbed at 18 months post-diagnosis due to dissemination of the disease. The literature on the extraneural metastasis of MB is also reviewed in the current study.

MiR-34a Inhibits Viability and Invasion of Human Papillomavirus-Positive Cervical Cancer Cells by Targeting E2F3 and Regulating Survivin.

OBJECTIVE: Previous studies confirmed that high-risk human papillomavirus (HR-HPV) infection is a risk factor of cervical cancer, and the infection was associated with significantly reduced miR-34a expression during carcinogenesis. However, the downstream targets of miR-34a and their roles are still not well understood. This study explored the regulative role of miR-34a on E2F3 and survivin expression and the viability and invasion of HPV-positive cervical cancer cells. METHODS: MiR-34a and survivin expression in 56 cases of HR-HPV-positive patients, 28 cases of HR-HPV-negative patients, and 28 normal cases without HR-HPV infections were measured. Human papillomavirus-18-positive HeLa cervical cancer cells and HPV-16-positive SiHa cells were used to explore the effect of miR-34a on cell viability and invasion. The molecular target of miR-34a was also explored in cervical cancer cells. RESULTS: The results showed that miR-34a overexpression could inhibit HPV-positive cancer cell viability, whereas its downregulation promoted cell viability. E2F3 is a direct target of miR-34a in HPV-positive cervical cancer cells. By targeting E2F3, miR-34a could regulate the expression of survivin. Thus, through regulating E2F3 and survivin, miR-34a could reduce the viability and invasion of HPV-positive cervical cancer cells. CONCLUSIONS: This study confirmed a novel miR-34a-E2F3-survivin axis in the tumor suppressor role of miR-34a in cervical cancer.

Early growth response 2 (Egr-2) expression is triggered by NF-κB activation.

Transcription factors are known to play multiple roles in cellular function. Investigators report that factors such as early growth response (Egr) protein and nuclear factor kappa B (NF-κB) are activated in the brain during cancer, brain injury, inflammation, and/or memory. To explore NF-κB activity further, we investigated the transcriptomes of hippocampal slices following electrical stimulation of NF-κB p50 subunit knockout mice (p50-/-) versus their controls (p50+/+). We found that the early growth response gene Egr-2 was upregulated by NF-κB activation, but only in p50+/+ hippocampal slices. We then stimulated HeLa cells and primary cortical neurons with tumor necrosis factor alpha (TNFα) to activate NF-κB and increase the expression of Egr-2. The Egr-2 promoter sequence was analyzed for NF-κB binding sites and chromatin immunoprecipitation (ChIP) assays were performed to confirm promoter occupancy in vivo. We discovered that NF-κB specifically binds to an NF-κB consensus binding site within the proximal promoter region of Egr-2. Luciferase assay demonstrated that p50 was able to transactivate the Egr-2 promoter in vitro. Small interfering RNA (siRNA)-mediated p50 knockdown corroborated other Egr-2 expression studies. We show for the first time a novel link between NF-κB activation and Egr-2 expression with Egr-2 expression directly controlled by the transcriptional activity of NF-κB.

RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.

Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCδ. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

Bryostatin analogue-induced apoptosis in mantle cell lymphoma cell lines.

The anti-cancer effects of bryostatin-1, a potent diacylglycerol analogue, have traditionally been attributed to its action on protein kinase C. However, we previously documented apoptosis in a B non-Hodgkin lymphoma cell line involving diacylglycerol analogue stimulation of Ras guanyl-releasing protein, a Ras activator, and Bim, a proapoptotic Bcl-2 family protein. To further explore the role of Bim, we examined several Bim-deficient B non-Hodgkin lymphoma cells for their responses to pico, a synthetic bryostatin-1-like compound. The Bim(-) mantle cell lymphoma cell lines Jeko-1, Mino, Sp53, UPN1, and Z138 and the Bim(+) cell line Rec-1, as well as the Burkitt lymphoma cells lines BL2 (Bim(-)) and Daudi (Bim(+)), were examined for their response to pico using assays for proliferation and apoptosis as well as biochemical methods for Ras guanyl-releasing proteins and Bcl-2 family members. With the exception of UPN1, mantle cell lymphoma cell lines underwent pico-induced apoptosis, as did BL2. In some cases, hallmarks of apoptosis were substantially diminished in the presence of mitogen-activated protein kinase kinase inhibitors. Pico treatment generally led to increased expression of proapoptotic Bik, although the absolute levels of Bik varied considerably between cell lines. A pico-resistant variant of Z138 exhibited decreased Bik induction compared to parental Z138 cells. Pico also generally decreased expression of anti-apoptotic Bcl-XL and Mcl1. Although, these changes in Bcl-2 family members seem unlikely to fully account for the differential behavior of the cell lines, our demonstration of a potent apoptotic process in most cell lines derived from mantle cell lymphoma encourages a re-examination of diacylglycerol analogues in the treatment of this subset of B non-Hodgkin lymphoma cases.

Will periodic intravenous injections of conditioned bone marrow cells effectively reduce atherosclerosis?

Maintenance of healthy arteries requires a balance between injuries to the arterial wall and processes of intrinsic arterial repair. Such repair requires the availability of progenitor cells that are local to the wall itself. Progenitor cells from distant reservoirs like the bone marrow may also contribute to repair. Arterial repair seems to degrade over a lifetime, particularly with risk factors such as smoking and diabetes. Hence, a potential preventive/therapeutic strategy for atherosclerosis could be transfusion of competent bone marrow cells (BMCs) to restore effective repair in the face of arterial injury and depleted endogenous repair reservoirs. The challenge with this strategy has been the reliable collection and/or generation of BMCs that support arterial repair. In this study, we describe a set of experiments to elucidate a method of culturing BMCs that robustly retards atherosclerosis development in apolipoprotein E knockout mice. Identifying such a method would represent an important step in developing cell-based treatments for patients with proclivity for developing atherosclerosis.

A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells.

OBJECTIVE: Bryostatin-1 and related diacylglycerol (DAG) analogues activate RasGRPs in lymphocytes, thereby activating Ras and mimicking some aspects of immune receptor signaling. To define the role of RasGRPs in lymphocyte apoptosis and to identify potential therapeutic uses for DAG analogues in lymphocyte disorders, we characterized the response of lymphoma-derived cell lines to DAG analogues. MATERIALS AND METHODS: Human lymphoma-derived B cell lines and mouse primary B cells were treated with bryostatin-1 or its synthetic analogue "pico." Ras signaling partners and Bcl-2 family members were studied with biochemical assays. Cellular responses were monitored using growth and apoptosis assays. RESULTS: Stimulation of B cells with DAG analogues results in activation of protein kinase C/RasGRP-Ras-Raf-Mek-Erk signaling and phosphorylation of the proapoptotic BH3-only protein Bim. In vitro, Bim is phosphorylated by Erk on sites previously associated with increased apoptotic activity. In Toledo B cells derived from a non-Hodgkin's lymphoma (B-NHL), DAG analogue stimulation leads to extensive apoptosis. Apoptosis can be suppressed by either downregulation of Bim or overexpression of Bcl-2. It is associated with the formation of Bak-Bax complexes and increased mitochondrial membrane permeability. Toledo B-NHL cell apoptosis shows a striking dependence on sustained signaling. CONCLUSION: In B cells, Erk activation leads directly to phosphorylation of Bim on sites associated with activation of Bim. In Toledo B-NHL cells, the dependence of apoptosis on sustained signaling suggests that Bcl-2 family members could interpret signal duration, an important determinant of B cell receptor-mediated negative selection. Certain cases of B-NHL might respond to DAG analogue treatment by the mechanism outlined here.

Molecular evidence for arterial repair in atherosclerosis.

Atherosclerosis is a chronic inflammatory process and progresses through characteristic morphologic stages. We have shown previously that chronically injecting bone-marrow-derived vascular progenitor cells can effect arterial repair. This repair capacity depends on the age of the injected marrow cells, suggesting a progressive decline in progenitor cell function. We hypothesized that the progression of atherosclerosis coincides with the deteriorating repair capacity of the bone marrow. Here, we ascribe patterns of gene expression that accurately and reproducibly identify specific disease states in murine atherosclerosis. We then use these expression patterns to determine the point in the disease process at which the repair of arteries by competent bone marrow cells ceases to be efficient. We show that the loss of the molecular signature for competent repair is concurrent with the initiation of atherosclerotic lesions. This work provides a previously unreported comprehensive molecular data set using broad-based analysis that links the loss of successful repair with the progression of a chronic illness.