Showing papers by "University of Louisville published in 2014"

The Relationship Between Entrepreneurship Education and Entrepreneurial Intentions: A Meta-Analytic Review

Abstract: The research on entrepreneurship education�entrepreneurial intentions has yielded mixed results. We meta-analyzed 73 studies with a total sample size of 37,285 individuals and found a significant but a small correlation between entrepreneurship education and entrepreneurial intentions (inline image). This correlation is also greater than that of business education and entrepreneurial intentions. However, after controlling for pre-education entrepreneurial intentions, the relationship between entrepreneurship education and post-education entrepreneurial intentions was not significant. We also analyzed moderators, such as the attributes of entrepreneurship education, students' differences, and cultural values. Our results have implications for entrepreneurship education scholars, program evaluators, and policy makers.

Analysis of defect generation in Ti–6Al–4V parts made using powder bed fusion additive manufacturing processes

Abstract: Ti–6Al–4V parts made using additive manufacturing processes such as selective laser melting (SLM) and electron beam melting (EBM) are subject to the inclusion of defects. This study purposely fabricated Ti–6Al–4V samples with defects by varying process parameters from the factory default settings in both SLM and EBM systems. Process parameters are classified according to their tendency to create certain types of porosity. Finally, defect characteristics are discussed with respect to defect generation mechanisms; and effective process windows for SLM and EBM system are discussed.

Dynamic population mapping using mobile phone data

Abstract: During the past few decades, technologies such as remote sensing, geographical information systems, and global positioning systems have transformed the way the distribution of human population is studied and modeled in space and time. However, the mapping of populations remains constrained by the logistics of censuses and surveys. Consequently, spatially detailed changes across scales of days, weeks, or months, or even year to year, are difficult to assess and limit the application of human population maps in situations in which timely information is required, such as disasters, conflicts, or epidemics. Mobile phones (MPs) now have an extremely high penetration rate across the globe, and analyzing the spatiotemporal distribution of MP calls geolocated to the tower level may overcome many limitations of census-based approaches, provided that the use of MP data is properly assessed and calibrated. Using datasets of more than 1 billion MP call records from Portugal and France, we show how spatially and temporarily explicit estimations of population densities can be produced at national scales, and how these estimates compare with outputs produced using alternative human population mapping methods. We also demonstrate how maps of human population changes can be produced over multiple timescales while preserving the anonymity of MP users. With similar data being collected every day by MP network providers across the world, the prospect of being able to map contemporary and changing human population distributions over relatively short intervals exists, paving the way for new applications and a near real-time understanding of patterns and processes in human geography.

Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy

Abstract: Background Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. Methods Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. Results Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1–negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic memb...

Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522

Abstract: Purpose Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). Patients and methods Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. Results Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v. 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v. 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v. 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v. 2.0%, respectively; P = .81), 3-year PFS (61.2% v. 58.9%, respectively; P = .76), 3-year OS (72.9% v. 75.8%, respectively; P = .32), locoregional failure (19.9% v. 25.9%, respectively; P = .97), or distant metastasis (13.0% v. 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v. 49.2%, respectively; P Conclusion Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

Digital innovation as a fundamental and powerful concept in the information systems curriculum

Abstract: The 50-year march of Moore's Law has led to the creation of a relatively cheap and increasingly easy-touse world-wide digital infrastructure of computers, mobile devices, broadband network connections, and advanced application platforms. This digital infrastructure has, in turn, accelerated the emergence of new technologies that enable transformations in how we live and work, how companies organize, and the structure of entire industries. As a result, it has become important for all business students to have a strong grounding in IT and digital innovation in order to manage, lead, and transform organizations that are increasingly dependent on digital innovation. Yet, at many schools, students do not get such grounding because the required information systems core class is stuck in the past. We present a vision for a redesigned IS core class that adopts digital innovation as a fundamental and powerful concept (FPC). A good FPC serves as both a foundational concept and an organizing principle for a course. We espouse a particularly broad conceptualization of digital innovation that allows for a variety of teaching styles and topical emphases for the IS core class. This conceptualization includes three types of innovation (i.e., process, product, and business model innovation), and four stages for the overall innovation process (i.e., discovery, development, diffusion, and impact). Based on this conceptualization, we examine the implications of adopting digital innovation as an FPC. We also briefly discuss broader implications relating to (1) the IS curriculum beyond the core class, (2) the research agenda for the IS field, and (3) the identity and legitimacy of IS in business schools.

Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans

Abstract: Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.

Search for a dark photon in e(+)e(-) collisions at BABAR.

Abstract: Dark sectors charged under a new Abelian interaction have recently received much attention in the context of dark matter models. These models introduce a light new mediator, the so-called dark photon (A^{'}), connecting the dark sector to the standard model. We present a search for a dark photon in the reaction e^{+}e^{-}→γA^{'}, A^{'}→e^{+}e^{-}, μ^{+}μ^{-} using 514 fb^{-1} of data collected with the BABAR detector. We observe no statistically significant deviations from the standard model predictions, and we set 90% confidence level upper limits on the mixing strength between the photon and dark photon at the level of 10^{-4}-10^{-3} for dark photon masses in the range 0.02-10.2 GeV. We further constrain the range of the parameter space favored by interpretations of the discrepancy between the calculated and measured anomalous magnetic moment of the muon.

The Physics of the B Factories

Abstract: This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C.

An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial.

Abstract: Background The HeartWare left ventricular assist device (HVAD, HeartWare Inc, Framingham, MA) is the first implantable centrifugal continuous-flow pump approved for use as a bridge to transplantation. An infrequent but serious adverse event of LVAD support is thrombus ingestion or formation in the pump. In this study, we analyze the incidence of pump thrombus, evaluate the comparative effectiveness of various treatment strategies, and examine factors pre-disposing to the development of pump thrombus. Methods The analysis included 382 patients who underwent implantation of the HVAD as part of the HeartWare Bridge to Transplant (BTT) and subsequent Continued Access Protocol (CAP) trial. Descriptive statistics and group comparisons were generated to analyze baseline characteristics, incidence of pump thrombus, and treatment outcomes. A multivariate analysis was performed to assess significant risk factors for developing pump thrombus. Results There were 34 pump thrombus events observed in 31 patients (8.1% of the cohort) for a rate of 0.08 events per patient-year. The incidence of pump thrombus did not differ between BTT and CAP. Medical management of pump thrombus was attempted in 30 cases, and was successful in 15 (50%). A total of 16 patients underwent pump exchange, and 2 underwent urgent transplantation. Five patients with a pump thrombus died after medical therapy failed, 4 of whom also underwent a pump exchange. Survival at 1 year in patients with and without a pump thrombus was 69.4% and 85.5%, respectively ( p = 0.21). A multivariable analysis revealed that significant risk factors for pump thrombus included a mean arterial pressure > 90 mm Hg, aspirin dose ≤ 81 mg, international normalized ratio ≤ 2, and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile level of ≥ 3 at implant. Conclusions Pump thrombus is a clinically important adverse event in patients receiving an HVAD, occurring at a rate of 0.08 events per patient-year. Significant risk factors for pump thrombosis include elevated blood pressure and sub-optimal anti-coagulation and anti-platelet therapies. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

Abstract: Rationale: We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.Objectives: We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.Methods: We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.Measurements and Main Results: Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3...

Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles

Abstract: Scope Exosomes, small vesicles participating in intercellular communication have been extensively studied recently; however, the role of edible plant derived exosomes in interspecies communication has not been investigated. Here, we investigate the biological effects of edible plant derived exosome-like nanoparticles (EPDEN) on mammalian cells.

Epidemiology of Low Back Pain in Adults

Abstract: Objective Low back pain affects many individuals. It has profound effects on well-being and is often the cause of significant physical and psychological health impairments. Low back pain also affects work performance and social responsibilities, such as family life, and is increasingly a major factor in escalating health-care costs. A global review of the prevalence of low back pain in the adult general population has shown its point prevalence to be approximately 12%, with a one-month prevalence of 23%, a one-year prevalence of 38%, and a lifetime prevalence of approximately 40%. Furthermore, as the population ages over the coming decades, the number of individuals with low back pain is likely to increase substantially. This comprehensive review is undertaken to assess the increasing prevalence of low back pain and the influence of comorbid factors, along with escalating costs. Materials and Methods A narrative review with literature assessment. Results In the USA, low back pain and related costs are escalating. Based on the available literature, it appears that the prevalence of low back pain continues to increase, along with numerous modalities and their application in managing low back pain. Comorbid factors with psychological disorders and multiple medical problems, including obesity, smoking, lack of exercise, increasing age, and lifestyle factors, are considered as risk factors for low back pain. Conclusion Although it has been alleged that low back pain resolves in approximately 80% to 90% of patients in about six weeks, irrespective of the administration or type of treatment, with only 5% to 10% of patients developing persistent back pain, this concept has been frequently questioned as the condition tends to relapse and most patients experience multiple episodes years after the initial attack.

The Increasing Incidence of Young-Onset Colorectal Cancer: A Call to Action

Abstract: In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.

Randomized Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity

Abstract: Purpose We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). Patients and Methods Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m 2 once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray’s test. Results In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. Conclusion When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification. J Clin Oncol 32:3858-3867. © 2014 by American Society of Clinical Oncology

ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1

Abstract: Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis

Abstract: Spermatogenesis in mammals is characterized by two waves of piRNA expression: one corresponds to classic piRNAs responsible for silencing retrotransponsons and the second wave is predominantly derived from nontransposon intergenic regions in pachytene spermatocytes, but the function of these pachytene piRNAs is largely unknown. Here, we report the involvement of pachytene piRNAs in instructing massive mRNA elimination in mouse elongating spermatids (ES). We demonstrate that a piRNA-induced silencing complex (pi-RISC) containing murine PIWI (MIWI) and deadenylase CAF1 is selectively assembled in ES, which is responsible for inducing mRNA deadenylation and decay via a mechanism that resembles the action of miRNAs in somatic cells. Such a highly orchestrated program appears to take full advantage of the enormous repertoire of diversified targeting capacity of pachytene piRNAs derived from nontransposon intergenic regions. These findings suggest that pachytene piRNAs are responsible for inactivating vast cellular programs in preparation for sperm production from ES.

Exosomes: A Novel Pathway of Local and Distant Intercellular Communication that Facilitates the Growth and Metastasis of Neoplastic Lesions

Abstract: Normal and diseased cells release bilayered membrane-bound nanovesicles into interstitial spaces and into bodily fluids. A subgroup of such microvesicles is called exosomes and is described in blood as 30 to 100 nm in diameter and as spherical to cup-shaped nanoparticles with specific surface molecular characteristics (eg, expression of the tetraspanins CD9, CD81, and CD63). Extracellular microvesicles provide local signals (eg, autocrine and paracrine) and distant endocrine signals to cells via the transfer of their contents, which include signal proteins, lipids, miRNAs, and functional mRNAs. Exosomes and related microvesicles also aid cells in exporting less-needed molecules and potentially harmful molecules, including drugs; in the case of neoplasia, the export of chemotherapeutic drugs may facilitate cellular chemoresistance. Cancers have adapted the exosome and related microvesicles as a pathway by which neoplastic cells communicate with each other (autocrine) and with nonneoplastic cells (paracrine and endocrine); via this pathway, cancer suppresses the immune system and establishes a fertile local and distant environment to support neoplastic growth, invasion, and metastases. Because exosomes mirror and bind to the cells from which they arise, they can be used for delivery of drugs, vaccines, and gene therapy, as biomarkers and targets. We review how exosomes and related extracellular microvesicles facilitate the progression and metastases of cancers and describe how these microvesicles may affect clinical care.

Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications

Abstract: . Purpose: To evaluate the relationship between signs and symptoms of dry eye disease (DED) in a clinic-based population. Methods: In a retrospective analysis, clinical signs and symptoms were evaluated for 344 subjects (n = 82, normal; n = 263, dry eye), across 11 sites from the EU and United States. Pearson correlations between signs and symptoms (r2) and an independent components analysis (ICA) mixing matrix were derived from the data set. Similar analysis was performed on an independent data set from 200 subjects in a previous study in Munich, Germany. Results: No correlations above r2 = 0.17 were found between any signs and symptoms, except for corneal and conjunctival staining, which reported an r2 = 0.36. In the multisite study, the average r2 for osmolarity (0.07), tear breakup time (0.12), Schirmer test (0.09), corneal (0.16) and conjunctival staining (0.17), meibomian grading (0.11) and Ocular Surface Disease Index® (0.11) were consistently low. Among patients who showed evidence of DED by consensus of clinical signs, only 57% reported symptoms consistent with a diagnosis of DED. Similar results were observed in the Munich-based study data set. Each component of the ICA mixing matrix exhibited minimal residual information. Conclusions: No consistent relationship was found between common signs and symptoms of DED. Each type of measurement provides distinct information about the condition of the ocular surface. These results also demonstrate that symptoms alone are insufficient for the diagnosis and management of DED and argue for a consensus of clinical signs that better reflect all aspects of the disease.

A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.

Abstract: Background DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1–4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results 35 patients were enrolled and treated. One patient (2.9 %) had a response to treatment. The response was dramatic (84 % reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient’s tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

Breaking bad: manipulation of the host response by Porphyromonas gingivalis.

Abstract: Recent metagenomic and mechanistic studies are consistent with a new model of periodontal pathogenesis. This model proposes that periodontal disease is initiated by a synergistic and dysbiotic microbial community rather than by a select few bacteria traditionally known as “periopathogens.” Low-abundance bacteria with community-wide effects that are critical for the development of dysbiosis are now known as keystone pathogens, the best-documented example of which is Porphyromonas gingivalis. Here, we review established mechanisms by which P. gingivalis interferes with host immunity and enables the emergence of dysbiotic communities. We integrate the role of P. gingivalis with that of other bacteria acting upstream and downstream in pathogenesis. Accessory pathogens act upstream to facilitate P. gingivalis colonization and co-ordinate metabolic activities, whereas commensals-turned pathobionts act downstream and contribute to destructive inflammation. The recent concepts of keystone pathogens, along with polymicrobial synergy and dysbiosis, have profound implications for the development of therapeutic options for periodontal disease.