Role of estrogen in treatment of female depression.

Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression's pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.

Porous Organic Polymers-Supported Zeigler-Natta Catalysts for Preparing Highly Isotactic Polypropylene with Broad Molecular Weight Distribution.

Porous organic polymers (POPs) have attracted much attention in numerous areas, including catalysis, adsorption and separation. Herein, POP supported Ziegler-Natta catalysts were designed for preparation of isotactic polypropylene (iPP). The POPs-based Ziegler-Natta catalysts exhibited the characteristic of broad molecular weight distribution (MWD > 11) with or without adding an extra internal electron donor. The added internal electron donor 3-methyl-5-tert-butyl-1,2-phenylene dibenzoate (ID-2) used in cat-2 showed good propylene polymerization activity of 15.3 × 106 g·PP/mol·Ti·h, high stereoregularity with 98.2% of isotacticity index and broad molecular weight distribution (MWD) of 12.3. Compared to the MgCl2-supported Ziegler-Natta catalysts (cat-4) with the same ID-2, cat-2 showed higher chain stereoregularity for propylene polymerization. As seen in the TREF results, the elution peak of PP-2 (124.0 °C, 91.7%) is 1.5 °C higher than the isotactic fraction from PP-4 (122.5 °C, 87.2%), and even 1.2 °C higher than PP-5 prepared from ID-3 with the characteristics of high stereoregularity. Moreover, the pentad methyl sequence mmmm of PP-2 (93.0%) from cat-2 is 0.5% higher than that of PP-4 from cat-4. XPS analysis revealed that the minute difference in binding energy of Ti, Mg, C and O atoms exist between the inorganic MgCl2 and the organic polymer based Z-N catalysts. The plausible interaction mechanism of active sites of Mg and Ti with the functional groups in the POP support and the added ID was proposed, which could be explained by their high stereoregularity and the broad molecular weight distribution of the POP-based Z-N catalysts.

Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses.

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host's DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

MiR-1471 protects the aggravation of non-small-cell lung carcinoma by targeting FOXL1.

This study detected the expression pattern of miR-1471 in non-small-cell lung cancer (NSCLC) tissues, and analyzed the prognostic significance of miR-1471 in NSCLC. Subsequently, potential targets of miR-1471 were screened for assessing the potential molecular mechanism in NSCLC. A total of 47 primary NSCLC cases treated by radical resection and systematic lymphadenectomy in the department of thoracic surgery were collected, as well as their clinical data. MiR-1471 levels in NSCLC tissues were detected by quantitative real-time polymerase chain reaction. The prognostic potential of miR-1471 in NSCLC was assessed by Kaplan-Meier method, followed by log-rank test. Potential target genes of miR-1471 and the binding sites were predicted by bioinformatics analysis, and screened for the optimal one. The binding relationship between miR-1471 and the target FOXL1 was examined by dual-luciferase reporter assay. Subsequently, biological functions of miR-1471 and FOXL1 in NSCLC cell functions were explored by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry. MiR-1471 was downregulated in NSCLC tissues and its level was correlated to TNM staging in NSCLC patients. Overall survival was poor in NSCLC patients expressing low level of miR-1471. Overexpression of miR-1471 attenuated proliferative ability and arrested cell cycle progression in G1/S phase. FOXL1 was confirmed to be the target gene binding miR-1471. Its expression pattern and biological functions in NSCLC cells were contrary to those of miR-1471. MiR-1471 is downregulated in NSCLC samples, which is related to TNM staging and prognosis in NSCLC patients. Therefore, miR-1471 suppresses the malignant aggravation of NSCLC via inhibiting the translation of FOXL1 mRNA. In addition, it could be used as an effective biomarker for predicting the prognosis in NSCLC.

Progress in Vaccination of Prophylactic Human Papillomavirus Vaccine.

The human papillomavirus (HPV) vaccine plays an important role in preventing a series of diseases caused by HPV. Recent studies have shown that as a primary prevention measure, it can considerably prevent HPV infection and HPV-associated cervical cancer. However, studies on the safety, efficacy, and coverage of the HPV vaccine remain insufficient, especially in developing countries. Therefore, in this review, we outlined the recent studies of the HPV vaccine in terms of immunogenicity, safety, efficacy, latest vaccination concepts, and strategies. This review may provide a theoretical basis for use of the HPV vaccine.

Biological role of GITR/GITRL in attributes and immune responses of macrophage.

Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL), a member of the tumor necrosis factor superfamily, is expressed in APCs and acts as a costimulatory molecule in the immune system. Although the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR)/GITRL system has been modulated to promote or decrease T cell-related responses in multiple diseases, studies in macrophages are limited. To address this issue, we compared the expression of GITRL in various types of macrophages and analyzed whether GITRL can affect the fundamental properties and major functions of these cells. Our results demonstrated that M1 polarized macrophages had the highest GITRL levels. Furthermore, GITRL overexpression skewed macrophage polarization toward the M1 phenotype, accelerating proliferation and migration and regulating phagocytosis and killing function. Moreover, GITRL-silenced cells showed a loss of these functions, further confirming its vital role. We also developed an acute peritonitis mouse model, in which macrophages were driven to differentiate into a proinflammatory phenotype with GITRL up-regulation, triggering a positive feedback loop. Our results provide molecular insight into how the GITR/GITRL system modulates innate immune responses, suggesting that manipulation of the GITR/GITRL system to treat diseases depends not only on T cell regulation but also on macrophage participation.

Toughened High-Flow Polypropylene with Polyolefin-based Elastomers.

Polyolefin is the most widely used and versatile commodity polymer. In this work, three types of polyolefin-based elastomers (PBEs) were adopted to toughen a high-flow polypropylene to improve its overall performance. The chain microstructures of these PBEs, including ethylene/1-octene (E/O) random copolymer from Dow Chemical's polyolefin elastomer (POE), olefin block copolymers (OBCs) of E/O from Dow, and ethylene/propylene random copolymer from ExxonMobil's propylene-based elastomer, were elucidated by GPC, 13C NMR, TREF, and DSC techniques. The mechanical, thermal and optical properties, and morphology analysis of the PP/PBE blends were also studied to investigate the toughening mechanism of these PBEs. The results showed that all three types of PBEs can effectively improve the Izod impact strength of the PP/PBE blends by the addition of the rubber compositions, at the cost of the stiffness. PBE-1 and PBE-2 were found to have a great stiffness-toughness balance with about 1700 MPa of flexural modulus, about 110 °C of HDT and 3.6 kJ/m2 of impact strength on the prepared PP/PBE blends by forming separated rubber phase and refined spherulite crystals. As a result, the OBC with alternating hard and soft segments could achieve a similar toughening effect as the E/P random copolymer. Surprisingly, no obvious rubber phase separation was observed in the PP/PBE-4 blend, which might be due to the good compatibility of the E/P random chains with the isotactic PP; therefore, the PP/PBE blend obtains great toughness performance and optical transparency with the highest Izod impact strength of 4.2 kJ/m2 and excellent transparency.

Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants.

Long interspersed nuclear elements (LINE-1) is now considered as the only active autonomous mobile DNA in humans, LINE-1 retrotransposition activities are associated with and fluctuate during cancer initiation and progression; however, the mechanism underlying the increased LINE-1 activity in cancer is poorly understood. SAMHD1 has been reported to be a potent inhibitor of LINE-1 retrotransposition, and SAMHD1 mutations are frequently associated with cancer development. To gain insights on whether cancer-related SAMHD1 mutants affect LINE-1 activity, we explored the biochemical and cellular properties of some human mutants known correlate with the development of cancer. Most of the tested SAMHD1 cancer-related mutations were defective in LINE-1 inhibition. Interestingly we also found that SAMHD1 mutant K288T was defective for dNTPase activity but showed potent activity against LINE-1 retrotransposition. These findings suggest that LINE-1 inhibition does not depend solely on the dNTPase activity of SAMHD1. In contrast, SAMHD1's ability to inhibit ORF2p-mediated LINE-1 RNP reverse transcription was correlated with SAMHD1-mediated LINE-1 inhibition. Together, our data could also facilitate the deeper understanding for the inhibition of endogenous LINE-1 elements by SAMHD1.

Effects of Berberine and Its Derivatives on Cancer: A Systems Pharmacology Review.

Numerous studies have shown that berberine and its derivatives demonstrate important anti-tumor effects. However, the specific underlying mechanism remains unclear. Therefore, based on systems pharmacology, this review summarizes the information available on the anti-tumor effects and mechanism of berberine and its derivatives. The action and potential mechanism of action of berberine and its derivatives when used in the treatment of complex cancers are systematically examined at the molecular, cellular, and organismic levels. It is concluded that, with further in-depth investigations on their toxicity and efficacy, berberine and its derivatives have the potential for use as drugs in cancer therapy, offering improved clinical efficacy and safety.

New Strategies for Therapeutic Cancer Vaccines.

BACKGROUND: Patients with low response rates to cancer vaccines, short duration of anti-tumor response after vaccination, and relatively weak curative effects are problems that have not been resolved effectively during the development and application of cancer vaccines. With the continuous improvement of knowledge and awareness regarding the immune system and cancer cells, many researches have helped to explain the reasons for poor vaccine efficacy. Input from researchers accompanied by some newly emerged strategies could bring hope to improve the therapeutic effects of vaccines. METHODS: Data were collected from Web of Science, Medline, Pubmed, through searching of these keywords: "cancer vaccine", "cancer stem cell", "targeted agent", "immune checkpoint blockade" and "neoantigen". RESULTS: It may be more effective in immunotherapy of human cancers, including cancer stem cell vaccines, combination vaccines with targeted agents or immune checkpoint blockade, and neoantigen-based vaccines. CONCLUSION: Personalized vaccines will become the mainstream solution of cancer treatment program with the continuous improvement of human understanding of the immune system and the progress of related experiments.

Liuweiwuling tablets attenuate BDL-induced hepatic fibrosis via modulation of TGF-ß/Smad and NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling (LWWL) tablets contain a six-herb Chinese formula and are commonly prescribed to facilitate nourishment of the liver and kidneys, clear away toxic materials and activate blood circulation. Administration of LWWL is well known for its protective effects on the liver and its capacity to confer long-term stability in patients exhibiting reduced transaminase levels. Clinical studies have reported that LWWL can also be used for the treatment of liver fibrosis with associated treatment regimens resulting in a concomitant reduction in transforming growth factor ß1 (TGF-ß1) levels in the serum of patients with hepatic fibrosis. TGF-ß1 plays a prominent role in stimulating liver fibrogenesis and this effect is mediated by myofibroblasts (MFB) derived from hepatic stellate cells (HSCs). It is likely that this phenomenon underpins the antifibrotic effects associated with LWWL. AIM: The purpose of this study was to investigate the antifibrotic effects and mechanisms pertaining to LWWL. METHODS: Hepatic fibrosis was induced in rats following bile duct ligation (BDL). Rats that underwent BDL received daily gavage administration of colchicine (0.2mg/kg per day), LWWL (0.4, 1.6, 6.4g/kg per day) or PBS (for the control group). Pathological changes in hepatic tissue were examined using hematoxylin and eosin (HE) and sirius red staining. Immunohistochemical analysis was performed to monitor α-SMA and type I collagen (Collagen I) protein expression. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analyses were used to monitor the expression of genes and proteins in the TGF-ß/Smad signaling pathway, including TGF-ß1, bone morphogenic protein and activin membrane-bound inhibitor (Bambi), Smad3, phosphorylated Smad3 (p-Smad3) and Smad7. We also monitored the expression of genes and proteins in the nuclear factor-κB (NF-κB) signaling pathway, including NF-κB p65, IκBα and phosphorylation of IκBα (p-IκBα), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1ß (IL-1ß). RESULTS: LWWL dose-dependently inhibited BDL-induced liver injury and hepatic fibrosis in rats. Furthermore, LWWL reduced liver tissue collagen deposition, hydroxyproline content, liver dysfunction and α-SMA expression in BDL-induced hepatic fibrosis rats. Moreover, LWWL markedly prevented activation of the TGF-ß/Smad signaling pathway by inhibiting expression of Smad2/3 and phosphorylation of Smad3, and upregulating the expression of Bambi and Smad7. In addition, LWWL regulated the expression of the inflammatory cytokines IL-1ß, TNF-α and IL-6 by inhibiting the activation of NF-κB p65 and the phosphorylation of IκBα, and increasing the expression of IκBα. CONCLUSIONS: LWWL can attenuate BDL-induced hepatic fibrosis in rats, and this effect may be due to modulation of the NF-κB-dependent inflammatory response and activation of HSC and TGF-ß/Smad-mediated synthesis and degradation of Collagen I.

Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-ß1 signaling pathways.

Oxymatrine (OMT) is able to effectively protect against hepatic fibrosis because of its anti-inflammatory property, while the underlying mechanism remains incompletely understood. In this study, forty rats were randomly divided into five groups: control group, model group (carbon tetrachloride, CCl4) and three OMT treatment groups (30, 60, 120mg/kg). After CCl4 alone, the fibrosis score was 20.2±0.8, and the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline content, and collagen I expression was elevated, but OMT blunted these parameters. Treatment with OMT prevented CCl4-induced increases in expression of pro-inflammatory and pro-fibrotic cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α, meanwhile OMT promoted the expression of anti-inflammatory and anti-fibrotic factors such as interleukin (IL)-10 and bone morphogenetic protein and activin membrane-bound inhibitor (Bambi). Moreover, lipopolysaccharides (LPS) and high mobility group box-1 (HMGB1), which activates Toll-like receptor 4 (TLR4) and modulate hepatic fibrogenesis through hepatic stellate cells (HSCs) or Kupffer cells, were significantly decreased by OMT treatment. These results were further supported by in vitro data. First, OMT suppressed the expression of TLR4 and its downstream pro-inflammatory cytokines, lowered the level of HMGB1, TGF-ß1 in macrophages. Then, OMT promoted Bambi expression and thereby inhibited activation of HSCs mediated by transforming growth factor (TGF)-ß1. In conclusion, this study showed that OMT could effectively attenuate the CCl4-induced hepatic fibrosis, and this effect may be due to modulation of TLR4-dependent inflammatory and TGF-ß1 signaling pathways.

[Effect of arterial infusion with methylene blue during total mesorectal excision on urination function and sexual function in male patients with rectal cancer].

OBJECTIVE: To explore the effect of arterial infusion with methylene blue during total mesorectal excision (TME) for better preservation of pelvic autonomic nerve on urination function and sexual function in male patients with rectal cancer. METHODS: A total of 68 male rectal cancer patients from Zhejiang Xiaoxing People's Hospital and 44 male rectal cancer patients from Guangdong Zhongshan Chenxinghai Hospital between June 2013 and June 2015 were prospectively enrolled. Patients were randomly divided into the trial group receiving arterial infusion with 8 ml of 1% methylene blue and the control group without artery infusion, with 56 cases in each group. All the patients underwent TME. Intra-operational lymph node removal and postoperative urination and sexual function (erection and ejaculation) were compared between two groups. RESULTS: The baseline data of the two groups were not significantly different (all P>0.05). As compared to the control group, the trial group had shorter operation time [(3.28±0.63) hours vs. (4.01±0.94) hours, P<0.01], less blood loss[(92.5±36.4) ml vs. (174.1±61.4) ml, P<0.01], and more lymph nodes harvested per patient (15.8±7.6 vs. 11.9±4.3, P<0.01). One year after operation, classI(, II(, III(, IIII( of urination was observed in 33 cases (58.9%), 15 cases (26.8%), 6 cases (10.7%), 2 cases (3.6%) in the trial group, while 24 (42.9%), 15 (26.8%), 12 (21.4%), 5 (8.9%) in the control group, which indicated that trial group was superior to control group(P<0.05). ClassI(, II(, III( of erection was observed in 36 cases (64.3%), 18 cases (32.1%), 2 cases(3.6%) in the trial group, while 25(44.6%), 23(41.1%), 8(14.3%) in the control group, which indicated that trial group was superior to the control group (P<0.05). ClassI(, II(, III( of ejaculation was found in 36 cases (62.5%), 18 cases (32.1%), 3 cases (5.4%) in the trial group, while 24 (42.9%), 22 (39.3%), 10(17.9%) in the control group, which also indicated that trial group was superior to the control group(P<0.05). CONCLUSIONS: In the treatment of male rectal cancer patients, TME combined with arterial infusion with methylene blue can facilitate the distinction of operation scope, which is beneficial to reduce damages to the pelvic nerve, leading to the protection of urinary function and sexual function. In addition, this procedure can result in shorter operation time, less operational blood loss and more lymph nodes harvested.

Expression of GITR Enhances Multiple Myeloma Cell Sensitivity to Bortezomib.

Recently tumor necrosis factor receptor super family member 18 (TNFRSF18, also called GITR) has been identified as a novel tumor suppressor gene in Multiple Myeloma (MM), undergoing aberrant DNA methylation-mediated gene expression silencing. Furthermore, the expression of GITR blocks canonical NF-κB activation in MM cells in response to TNFα. Bortezomib, a proteasome inhibitor, can induce NF-κB activation, which may significantly influence the drug response in MM patients. In this study, we aim to elucidate if GITR status is associated with response to Bortezomib in MM cells through regulating GITR mediated NF-κB blockade. We found that GITR was significantly downregulated in MM patients and cell lines. Overexpression of GITR inhibited non-canonical NF-κB activation induced by TNFα. Moreover, NF-κB inhibitor induced apoptosis in GITR-deficient MM cells in response to TNFα. In addition, overexpression of GITR could inhibit Bortezomib-induced NF-κB activation and enhance the cytotoxicity of Bortezomib in GITR-deficient MM cell line (MM1.S). In contrast, knockdown of GITR attenuated the cytotoxic effect of Bortezomib on GITR proficient MM (RPMI) cell line and increased NF-κB activation. Finally, overexpression of GITR enhanced the sensitivity to Bortezomib in co-culture with bone marrow stromal cells and significantly reduced the tumor growth in MM1.S xenograft mice. In conclusion, we demonstrated that GITR expression can enhance the sensitivity to Bortezomib by inhibiting Bortezomib-induced NF-κB activation.

Effect of dicycloplatin, a novel platinum chemotherapeutical drug, on inhibiting cell growth and inducing cell apoptosis.

Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA) of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS), collapse of mitochondrial membrane potential (Δψm), release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH) was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.

Analysis of retinoblastoma age incidence data using a fully stochastic cancer model.

Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this article, we examine the validity of the two-hit theory for RB by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of RB for the period 1962-2000 in Great Britain (England, Scotland and Wales). The population incidence of RB is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of RB, in support of Knudson's two-hit hypothesis.

Parameter identifiability and redundancy: theoretical considerations.

BACKGROUND: Models for complex biological systems may involve a large number of parameters. It may well be that some of these parameters cannot be derived from observed data via regression techniques. Such parameters are said to be unidentifiable, the remaining parameters being identifiable. Closely related to this idea is that of redundancy, that a set of parameters can be expressed in terms of some smaller set. Before data is analysed it is critical to determine which model parameters are identifiable or redundant to avoid ill-defined and poorly convergent regression. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we outline general considerations on parameter identifiability, and introduce the notion of weak local identifiability and gradient weak local identifiability. These are based on local properties of the likelihood, in particular the rank of the Hessian matrix. We relate these to the notions of parameter identifiability and redundancy previously introduced by Rothenberg (Econometrica 39 (1971) 577-591) and Catchpole and Morgan (Biometrika 84 (1997) 187-196). Within the widely used exponential family, parameter irredundancy, local identifiability, gradient weak local identifiability and weak local identifiability are shown to be largely equivalent. We consider applications to a recently developed class of cancer models of Little and Wright (Math Biosciences 183 (2003) 111-134) and Little et al. (J Theoret Biol 254 (2008) 229-238) that generalize a large number of other recently used quasi-biological cancer models. CONCLUSIONS/SIGNIFICANCE: We have shown that the previously developed concepts of parameter local identifiability and redundancy are closely related to the apparently weaker properties of weak local identifiability and gradient weak local identifiability--within the widely used exponential family these concepts largely coincide.

Parameter identifiability and redundancy in a general class of stochastic carcinogenesis models.

BACKGROUND: Heidenreich et al. (Risk Anal 1997 17 391-399) considered parameter identifiability in the context of the two-mutation cancer model and demonstrated that combinations of all but two of the model parameters are identifiable. We consider the problem of identifiability in the recently developed carcinogenesis models of Little and Wright (Math Biosci 2003 183 111-134) and Little et al. (J Theoret Biol 2008 254 229-238). These models, which incorporate genomic instability, generalize a large number of other quasi-biological cancer models, in particular those of Armitage and Doll (Br J Cancer 1954 8 1-12), the two-mutation model (Moolgavkar et al. Math Biosci 1979 47 55-77), the generalized multistage model of Little (Biometrics 1995 51 1278-1291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226-16231). METHODOLOGY/PRINCIPAL FINDINGS: We show that in the simpler model proposed by Little and Wright (Math Biosci 2003 183 111-134) the number of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing previous results of Heidenreich et al. (Risk Anal 1997 17 391-399) for the two-mutation model. For the more general model of Little et al. (J Theoret Biol 2008 254 229-238) the number of identifiable combinations of parameters is at most less than the number of biological parameters, where is the number of destabilization types, thereby also generalizing all these results. Numerical evaluations suggest that these bounds are sharp. We also identify particular combinations of identifiable parameters. CONCLUSIONS/SIGNIFICANCE: We have shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also identify particular combinations of identifiable parameters. These results are of theoretical interest, but also of practical significance to anyone attempting to estimate parameters for this large class of cancer models.

A stochastic carcinogenesis model incorporating multiple types of genomic instability fitted to colon cancer data.

A generalization of the two-mutation stochastic carcinogenesis model of Moolgavkar, Venzon and Knudson and certain models constructed by Little [Little, M.P. (1995). Are two mutations sufficient to cause cancer? Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll. Biometrics 51, 1278-1291] and Little and Wright [Little, M.P., Wright, E.G. (2003). A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data. Math. Biosci. 183, 111-134] is developed; the model incorporates multiple types of progressive genomic instability and an arbitrary number of mutational stages. The model is fitted to US Caucasian colon cancer incidence data. On the basis of the comparison of fits to the population-based data, there is little evidence to support the hypothesis that the model with more than one type of genomic instability fits better than models with a single type of genomic instability. Given the good fit of the model to this large dataset, it is unlikely that further information on presence of genomic instability or of types of genomic instability can be extracted from age-incidence data by extensions of this model.

Stochastic modelling of colon cancer: is there a role for genomic instability?

Three stochastic models of genomic instability recently developed by Little and Wright (Math. Biosci., (2003) 183, 111-34), with two, three and five stages, and the two-stage genomic instability model of Nowak et al. (Proc. Natl Acad. Sci. USA, (2002) 99, 16226-16231) are compared with the four-stage model proposed by Luebeck and Moolgavkar (Proc. Natl Acad. Sci. USA, (2002) 99, 15095-15100) that does not assume such an instability mechanism. All models are fitted to US colon cancer incidence data. The best fitting models are the two-stage model of Nowak et al. and the two-stage model of Little and Wright, with the four-stage model of Luebeck and Moolgavkar not markedly inferior. The fits of the three-stage and five-stage models are somewhat worse (P<0.05), the five-stage model fitting particularly poorly (P<0.01). Both optimal genomic instability models predict cellular mutation rates that are at least 10 000 times higher after genomic destabilization, for both sexes. Therefore, the results of this paper are somewhat at variance with those of previous analyses of Little and Wright in suggesting that equivalently good fit may be obtained by models that do not assume a role for genomic destabilization in the induction of colon cancer as for those that do.