RESUMEN
Haemophilus parainfluenzae (Hp) is a Gram-negative, highly prevalent, and abundant commensal in the human oral cavity, and an infrequent extraoral opportunistic pathogen. Hp occupies multiple niches in the oral cavity, including the supragingival plaque biofilm. Little is known about how Hp interacts with its neighbors in healthy biofilms nor its mechanisms of pathogenesis as an opportunistic pathogen. To address this, we identified the essential genome and conditionally essential genes in in vitro biofilms aerobically and anaerobically. Using transposon insertion sequencing (TnSeq) with a highly saturated mariner transposon library in two strains, the ATCC33392 type-strain (Hp 392) and oral isolate EL1 (Hp EL1), we show that the essential genomes of Hp 392 and Hp EL1 are composed of 395 (20%) and 384 (19%) genes, respectively. The core essential genome, consisting of 341 (17%) essential genes conserved between both strains, was composed of genes associated with genetic information processing, carbohydrate, protein, and energy metabolism. We also identified conditionally essential genes for aerobic and anaerobic biofilm growth, which were associated with carbohydrate and energy metabolism in both strains. RNAseq analysis determined that most genes upregulated during anaerobic growth are not essential for Hp 392 anaerobic survival. The completion of this library and analysis under these conditions gives us a foundational insight into the basic biology of H. parainfluenzae in differing oxygen conditions, similar to its in vivo habitat. This library presents a valuable tool for investigation into conditionally essential genes for an organism that lives in close contact with many microbial species in the human oral habitat.IMPORTANCEHaemophilus parainfluenzae is a highly abundant human commensal microbe, present in most healthy individuals where it colonizes the mouth. H. parainfluenzae correlates with good oral health and may play a role in preservation of healthy host status. Also, H. parainfluenzae can cause opportunistic infections outside of the oral cavity. To date, little is known about how H. parainfluenzae colonizes the human host, despite being such a frequent and abundant part of our human microbiome. Here, we demonstrate the creation and use of a powerful tool, a TnSeq library, used to identify genes necessary for both the outright growth of this organism and also genes conditionally essential for growth in varying oxygen status which it can encounter in the human host. This tool and these data serve as a foundation for further study of this relatively unknown organism that may play a role in preserving human health.
RESUMEN
Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-ß triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Interferón Tipo I , Melanoma , Receptor de Muerte Celular Programada 1 , Receptor de Interferón alfa y beta , Transducción de Señal , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/genética , Melanoma/metabolismo , Humanos , Receptor de Interferón alfa y beta/metabolismo , Receptor de Interferón alfa y beta/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Ratones , Interferón Tipo I/metabolismo , Factor de Transcripción STAT1/metabolismo , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/genética , Interferón beta/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quinasas Janus/metabolismo , Ratones Endogámicos C57BL , Interferón-alfa/farmacología , Interferón-alfa/metabolismo , FemeninoRESUMEN
PURPOSE: To estimate the risk of hepatobiliary infection, including endoTIPSitis, liver abscesses, and cholangitis, after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with prior biliary intervention. MATERIALS AND METHODS: This multi-institution, retrospective study identified 76 patients (n = 48 males; mean age, 54.9 years; mean Model for End-stage Liver Disease [MELD] score, 13.2; n = 45 for ascites and n = 23 for varices; n = 31 with prior liver transplantation) among 2,130 (3.6%) undergoing TIPS creation who had prior biliary intervention (n = 19 bilioenteric anastomoses, n = 35 sphincterotomies, n = 28 internal plastic stent placements, n = 4 internal metal stent placements, and n = 6 percutaneous biliary drain placements). The baseline risk of post-TIPS creation hepatobiliary infection was estimated from a control group of 1,202 TIPS creation procedures in patients without prior biliary intervention. RESULTS: Eleven (14.5%) of 76 patients developed hepatobiliary infection after TIPS creation, including 7 with endoTIPSitis, 4 with hepatic abscesses, and 2 with cholangitis. The 30-day risk of infection was 10.9% (95% confidence interval [CI], 3.5%-17.8%), significantly higher than the 0.4% risk (95% CI, 0.1%-0.8%) observed in patients without prior biliary intervention (hazard ratio [HR], 25.56; 95% CI, 8.36-78.13; P < .001). All types of biliary intervention were associated with increased risk of infection, with bilioenteric anastomoses conferring the highest risk. Paradoxically, among patients with prior biliary intervention, use of postprocedural antibiotic prophylaxis was associated with an increased infection risk (HR, 19.85; 95% CI, 2.44-161.50; P = .005). Microbial culture data showed high rates of Enterococcus, Klebsiella, and Candida species. CONCLUSIONS: Prior biliary intervention was associated with a 10.9% risk of hepatobiliary infection, including endoTIPSitis, liver abscess, and cholangitis, within 30 days after TIPS creation.
Asunto(s)
Colangitis , Absceso Hepático , Derivación Portosistémica Intrahepática Transyugular , Humanos , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Factores de Riesgo , Colangitis/etiología , Anciano , Absceso Hepático/etiología , Absceso Hepático/microbiología , Resultado del Tratamiento , Adulto , Factores de Tiempo , Medición de Riesgo , Estados Unidos , StentsRESUMEN
Haemophilus parainfluenzae ( Hp ) is a Gram-negative, pleomorphic rod, highly prevalent and abundant as a commensal in the human oral cavity, and an infrequent extraoral opportunistic pathogen. Hp occupies multiple niches in the oral cavity, including the tongue dorsum, keratinized gingiva, and the supragingival plaque biofilm. As a member of the HACEK group, Hp is also known to cause infective endocarditis. Additionally, case reports have identified Hp as the causative agent of meningitis, septic arthritis, chronic osteomyelitis, septicemia, and a variety of other infectious diseases. Little is known about how Hp interacts with its neighbors in the healthy biofilm nor about its mechanisms of pathogenesis as an extraoral opportunistic pathogen. To address these unknowns, we identified the essential genomes of two Hp strains and the conditionally essential genes for their growth in in vitro biofilms aerobically and anaerobically. Using transposon insertion sequencing (TnSeq) with a highly saturated mariner transposon library in two strains, the ATCC33392 type-strain ( Hp 392) and a commensal oral isolate EL1 ( Hp EL1), we show that the essential genome of Hp 392 and Hp EL1 is composed of 395 and 384 genes, respectively. The core essential genome, consisting of 341 essential genes conserved between both strains, was composed of genes associated with genetic information processing, carbohydrate, protein, and energy metabolism. We also identified conditionally essential genes for aerobic and anaerobic biofilm growth, which were associated with carbohydrate and energy metabolism in both strains of Hp . Additionally, RNAseq analysis determined that most genes upregulated during anaerobic growth are not essential for Hp 392 anaerobic biofilm survival. The completion of this library and analysis under these conditions gives us a foundational insight into the basic biology of H. parainfluenzae in differing oxygen conditions, similar to its in vivo oral habitat. Further, the creation of this library presents a valuable tool for further investigation into conditionally essential genes for an organism that lives in close contact with many microbial species in the human oral habitat.
RESUMEN
BACKGROUND: Aseptic humeral stem loosening is an uncommon complication of shoulder arthroplasty, and its presence has been considered a highly specific predictor of prosthetic joint infection (PJI). Literature on aseptic humeral stem loosening is sparse. The primary purpose of this study was to determine the rate of aseptic humeral loosening in revision shoulder arthroplasty. Secondarily, we sought to identify predictors of septic and aseptic humeral loosening. METHODS: Our institutional revision shoulder arthroplasty database was reviewed. Inclusion criteria were patients with humeral stem loosening as indicated in the operative report. Patient demographics, index surgery and indication, revision surgery and indication, and operative data were recorded. Charts were manually reviewed, and PJI scores were calculated using the International Consensus Meeting scoring criteria. International Consensus Meeting classifications of PJI "unlikely" and "possible" were considered aseptic, and PJI "probable" and "definite" were considered septic. Statistical analysis was performed to determine associations between the abovementioned variables and aseptic humeral loosening. RESULTS: Forty-six patients with 48 shoulders were included in our analysis. Ten cases (21%) were classified as definite PJI, 13 cases (27%) were classified as probable PJI, 4 cases (8%) were classified as possible PJI, and 21 cases (44%) were classified as PJI unlikely. On analysis of stem design, there were no statistically significant associations with aseptic loosening; although, a lack of proximal porous ingrowth surface trended toward higher rates of aseptic loosening in all patients and in anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) subgroup analyses. In the index RTSA subgroup, aseptic loosening was associated with female sex (P = .005). Seventeen of 39 shoulders (44%) that underwent either index ATSA or RTSA demonstrated concomitant glenoid loosening. The absence of glenoid loosening was associated with aseptic humeral loosening in index ATSA and RTSA (P < .001). CONCLUSION: Fifty-two % of revision shoulder arthroplasty cases with humeral loosening performed at our institution were aseptic. There appear to be distinct demographic and radiographic factors that are more commonly associated with aseptic as opposed to septic humeral loosening. Our data demonstrate that demographic predictors of aseptic loosening of RTSA include female sex. The absence of glenoid component loosening is associated with aseptic humeral loosening and concomitant glenoid loosening is associated with septic humeral loosening. Understanding of these factors can guide the preoperative index of suspicion for PJI in the setting of humeral stem loosening.
Asunto(s)
Artroplastía de Reemplazo de Hombro , Falla de Prótesis , Infecciones Relacionadas con Prótesis , Reoperación , Prótesis de Hombro , Humanos , Femenino , Masculino , Anciano , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/cirugía , Artroplastía de Reemplazo de Hombro/efectos adversos , Persona de Mediana Edad , Prótesis de Hombro/efectos adversos , Estudios Retrospectivos , Anciano de 80 o más Años , Húmero/cirugía , Articulación del Hombro/cirugía , AdultoRESUMEN
BACKGROUND: Despite 2-stage revision being a common treatment for elbow prosthetic joint infection (PJI), failure rates are high. The purpose of this study was to report on a single institution's experience with 2-stage revisions for elbow PJI and determine risk factors for failed eradication of infection. The secondary purpose was to determine risk factors for needing allograft bone at the second stage of revision in the setting of compromised bone stock. METHODS: We retrospectively analyzed all 2-stage revision total elbow arthroplasties (TEAs) performed for infection at a single institution between 2006 and 2020. Data collected included demographics and treatment course prior to, during, and after 2-stage revision. Radiographs obtained after explantation and operative reports were reviewed to evaluate for partial component retention and incomplete cement removal. The primary outcome was failed eradication of infection, defined as the need for repeat surgery to treat infection after the second-stage revision. The secondary outcome was the use of allograft for compromised bone stock during the second-stage revision. Risk factors for both outcomes were determined. RESULTS: Nineteen patients were included. Seven patients (37%) had either the humeral or ulnar component retained during the first stage, and 10 (53%) had incomplete removal of cement in either the humerus or ulna. Nine patients (47%) had allograft strut used during reimplantation and reconstruction. Nine patients (47%) failed to eradicate the infection after 2-stage revision. Demographic data were similar between the repeat-infection and nonrepeat-infection groups. Six patients (60%) with retained cement failed compared with 3 patients (33%) with full cement removal (P = .370). Two patients (29%) with a retained component failed compared to 7 patients (58%) with full component removal (P = .350). Allograft was used less frequently when a well-fixed component or cement was retained, with no patients with a retained component needing allograft compared to 9 with complete component removal (P = .003). Three patients (30%) with retained cement needed allograft, compared with 6 patients (67%) who had complete cement removal (P = .179). CONCLUSION: Nearly half of the patients failed to eradicate infection after 2-stage revision. The data did not demonstrate a clear association between retained cement or implants and risk of recurrent infection. Allograft was used less frequently when a component and cement were retained, possibly serving as a proxy for decreased bone loss during the first stage of revision. Therefore, the unclear benefit of removing well-fixed components and cement need to be carefully considered as it likely leads to compromised bone stock that complicates the second stage of revision.
Asunto(s)
Artroplastia de Reemplazo de Codo , Infecciones Relacionadas con Prótesis , Reoperación , Humanos , Reoperación/métodos , Masculino , Femenino , Estudios Retrospectivos , Infecciones Relacionadas con Prótesis/cirugía , Infecciones Relacionadas con Prótesis/etiología , Artroplastia de Reemplazo de Codo/métodos , Artroplastia de Reemplazo de Codo/efectos adversos , Anciano , Persona de Mediana Edad , Insuficiencia del Tratamiento , Factores de Riesgo , Articulación del Codo/cirugía , Prótesis de Codo , Trasplante Óseo/métodos , Anciano de 80 o más AñosAsunto(s)
Carcinoma de Células Escamosas , Neoplasias Cutáneas , Linfocitos T Citotóxicos , Linfocitos T Colaboradores-Inductores , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Agotamiento de Células T , Linfocitos T Citotóxicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
BACKGROUND: Nonsurgical management of chronic, degenerative rotator cuff tears (RCTs) can be an effective treatment strategy, but there is limited evidence to support conservative treatment of acute, traumatic RCTs. The objective of this study was to assess clinical outcomes and predictors of treatment success in patients with traumatic RCTs who elected for initial nonoperative treatment. METHODS: Patients from a single institution were retrospectively identified using diagnostic codes for traumatic RCTs followed by confirmed initial treatment with ≥2 months of physical therapy. The exclusion criteria included surgery within 2 months of injury and greater than grade I fatty infiltration on magnetic resonance imaging. At minimum 2-year follow-up, patients were contacted by telephone to collect interval surgical history and standardized patient-reported outcomes. Physical therapy was considered to have failed in all those who underwent surgical treatment and those with satisfaction ratings of "moderately dissatisfied" or "very dissatisfied." RESULTS: Follow-up outcomes were obtained in 40 of 49 patients (82%), with an average follow-up time of 4.2 years. Of the RCTs, 9 (22%) were small (<1 cm), 22 (54%) were medium (>1 cm to <3 cm), and 9 (22%) were large (>3 cm to <5 cm). Grade I fatty infiltration was seen on 25% of magnetic resonance imaging scans (n = 10). Rotator cuff repair was performed in 18 patients (45%) following an average of 6 months of nonoperative treatment (range, 3-12 months). Nonoperative treatment was determined to have failed in 23 of 40 patients (58%) in total. Conservative management was more likely to fail in patients with multiple tendons torn (P = .014). Tear size and retraction were not significantly different between patients who underwent surgery and those who did not. Patients who underwent surgical management had an 83% satisfaction rate at final follow-up compared with a 55% satisfaction rate for patients who did not undergo surgery (P = .054). There was no statistically significant difference in the American Shoulder and Elbow Surgeons score or visual analog scale score between these groups. Although patients who underwent surgery had a higher mean Single Alpha Numeric Evaluation score (86.3 vs. 75.1, P = .041), this difference was below the previously established minimal clinically important difference. CONCLUSION: Nonoperative treatment remains a viable option for certain patients with traumatic RCTs; however, the results of our study demonstrate a considerable early failure rate. This study further supports historical literature demonstrating reliably successful outcomes with surgical treatment of acute, traumatic RCTs.
Asunto(s)
Lesiones del Manguito de los Rotadores , Humanos , Lesiones del Manguito de los Rotadores/terapia , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Resultado del Tratamiento , Tratamiento Conservador/métodos , Adulto , Modalidades de Fisioterapia , Estudios de SeguimientoRESUMEN
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.
Asunto(s)
Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Antígeno B7-H1 , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/genética , Receptor de Muerte Celular Programada 1 , Especies Reactivas de Oxígeno , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Serina-Treonina Quinasas TORRESUMEN
Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.
Asunto(s)
Profármacos , Cicatrización de Heridas , Humanos , Profármacos/farmacología , Vendajes , Becaplermina/farmacología , InflamaciónRESUMEN
BACKGROUND: Hyperglycemia is a known risk factor for tendon degeneration due to oxidative stresses from production of advanced glycosylation end products. In patients with diabetes mellitus (DM), analysis of glycated hemoglobin (HbA1c) provides a 3-month window into a patient's glucose control. No guidelines exist for ideal preoperative HbA1c and glucose control prior to arthroscopic rotator cuff repair. This study evaluated if a critical HbA1c level is associated with reoperation following arthroscopic rotator cuff repair. METHODS: We retrospectively evaluated patients with DM who underwent primary arthroscopic rotator cuff repair from January 2014 to December 2018 at a single institution. Patients required a preoperative HbA1c within 3 months of surgery. Medical records were queried to evaluate for reoperation and identify the subsequent procedures performed. Univariate statistical analysis was performed to assess factors associated with reoperation (P < .05 considered significant). Threshold, area under the curve (AUC), analysis was performed to assess if a critical HbA1c value was associated with reoperation. RESULTS: A total of 402 patients met inclusion criteria. Patients had an average age of 65.5 years (range 40-89) at time of surgery; 244 (60.6%) patients were male; and average body mass index was 32.96 ± 5.81. Mean HbA1c was 7.36 (range 5.2-12). Thirty-three patients (8.2%) underwent subsequent reoperation. Six patients (1.5%) underwent capsular release and lysis of adhesions, 20 patients (5.0%) underwent a revision rotator cuff surgery, combination revision rotator cuff repair and lysis of adhesions, graft-augmented revision repair, or superior capsular reconstruction, and 7 patients (1.7%) underwent revision to reverse shoulder arthroplasty (1.7%). There were no cases of reoperation for infection. On AUC analysis, no critical HbA1c value was identified to predispose to reoperation. Interestingly, elevated preoperative American Society of Anesthesiologists (ASA) physical status classification score (2.8 vs. 2.28, P = .001) was associated with a higher reoperation rate. DISCUSSION: In patients with DM, preoperative HbA1c is not a predictive factor for surgical failure requiring reoperation. Stable glycemic control is important to a patient's overall health and may play a role in minimizing postoperative medical complications, but an elevated preoperative HbA1c should not be a strict surgical contraindication for arthroscopic rotator cuff repair. In patients with DM, an elevated ASA score is associated with an increased rate of subsequent reoperation; diabetic patients should be counseled accordingly.
Asunto(s)
Diabetes Mellitus , Lesiones del Manguito de los Rotadores , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Manguito de los Rotadores/cirugía , Lesiones del Manguito de los Rotadores/complicaciones , Lesiones del Manguito de los Rotadores/cirugía , Reoperación , Resultado del Tratamiento , Estudios Retrospectivos , Glucemia , Artroscopía/métodosRESUMEN
The study of human commensal bacteria began with the first observation of prokaryotes >340 years ago. Since then, the study of human-associated microbes has been justifiably biased toward the study of infectious pathogens. However, the role of commensal microbes has in recent years begun to be understood with some appreciation of them as potential protectors of host health rather than bystanders. As our understanding of these valuable microbes grows, it highlights how much more remains to be learned about them and their roles in maintaining health. We note here that a thorough framework for the study of commensals, both in vivo and in vitro is overall lacking compared to well-developed methodologies for pathogens. The modification and application of methods for the study of pathogens can work well for the study of commensals but is not alone sufficient to properly characterize their relationships. This is because commensals live in homeostasis with the host and within complex communities. One difficulty is determining which commensals have a quantifiable impact on community structure and stability as well as host health, vs benign microbes that may indeed serve only as bystanders. Human microbiomes are composed of bacteria, archaea, fungi, and viruses. This review focuses particularly on oral bacteria, yet many of the principles of commensal impacts on host health observed in the mouth can translate well to other host sites. Here, we discuss the value of commensals, the shortcomings involved in model systems for their study, and some of the more notable impacts they have upon not only each other but host health.
Asunto(s)
Microbiota , Simbiosis , Humanos , Bacterias/genética , Boca/microbiología , HongosRESUMEN
Haemophilus parainfluenzae is a Gram-negative bacterium that colonizes the mouth and the upper respiratory tract. Here, we report the genome sequence of H. parainfluenzae strain EL1 isolated from healthy supragingival plaque. This strain is used as a representative commensal of the oral microbiota.
RESUMEN
IMPORTANCE: As the microbiome era matures, the need for mechanistic interaction data between species is crucial to understand how stable microbiomes are preserved, especially in healthy conditions where the microbiota could help resist opportunistic or exogenous pathogens. Here we reveal multiple mechanisms of interaction between two commensals that dictate their biogeographic relationship to each other in previously described structures in human supragingival plaque. Using a novel variation for chemical detection, we observed metabolite exchange between individual bacterial cells in real time validating the ability of these organisms to carry out metabolic crossfeeding at distal and temporal scales observed in vivo. These findings reveal one way by which these interactions are both favorable to the interacting commensals and potentially the host.
Asunto(s)
Corynebacterium , Streptococcus mitis , Humanos , Streptococcus mitis/genética , SimbiosisRESUMEN
Lack of surgical access severely harms countless populations in many low- and middle-income countries (LMICs). Many types of surgery could be fulfilled by the plastic surgeon, as populations in these areas often experience trauma, burns, cleft lip and palate, and other relevant medical issues. Plastic surgeons continue to contribute significant time and energy to global health, primarily by participating in short mission trips intended to provide many surgeries in a short time frame. These trips, while cost-effective for lack of long-term commitments, are not sustainable as they require high initial costs, often neglect to educate local physicians, and can interfere with regional systems. Education of local plastic surgeons is a key step toward creating sustainable plastic surgery interventions worldwide. Virtual platforms have grown popular and effective-particularly due to the coronavirus disease 2019 pandemic-and have shown to be beneficial in the field of plastic surgery for both diagnosis and teaching. However, there remains a large potential to create more extensive and effective virtual platforms in high-income nations geared to educate plastic surgeons in LMICs to lower costs and more sustainably provide capacity to physicians in low access areas of the world.
Le manque d'accès à la chirurgie nuit sévèrement aux vastes populations de nombreux pays à revenus intermédiaires et faibles (PRIF). De nombreux types d'interventions chirurgicales pourraient être exécutés par les chirurgiens plastiques, car les populations de ces régions ont souvent des traumatismes, des brûlures, des fentes labio-palatines et d'autres problèmes médicaux pertinents. La chirurgie plastique continue d'accorder beaucoup de temps et d'énergie à la santé globale, principalement en participant à de courtes missions ayant pour but de résoudre de nombreux problèmes chirurgicaux dans un court laps de temps. Ces voyages, bien que rentables et influenceurs à court terme, n'ont pas d'effet durable, car ils ont des coûts initiaux élevés, négligent souvent d'éduquer les médecins locaux et peuvent perturber les systèmes régionaux. La formation de chirurgiens plastiques locaux est une étape essentielle pour la création d'interventions de chirurgie plastique durables dans le monde. Les plateformes virtuelles sont devenues populaires et efficaces, en particulier à cause de la pandémie de COVID-19, et ont montré leurs avantages dans le champ de la chirurgie plastique en matière de diagnostic et d'enseignement des divers facteurs de chirurgie plastique. Il existe un vaste potentiel pour la création de plateformes virtuelles permettant à des experts des pays à revenus élevés de former des chirurgiens plastiques de PRIF afin d'offrir des moyens plus rentables et durables à ces médecins exerçant dans des régions du monde où l'accès aux soins est plus limité.
RESUMEN
The human oral microbiome heavily influences the status of oral and systemic diseases through different microbial compositions and complex signaling between microbes. Recent evidence suggests that investigation of interactions between oral microbes can be utilized to understand how stable communities are maintained and how they may preserve health. Herein, we investigate two highly abundant species in the human supragingival plaque, Streptococcus mitis and Corynebacterium matruchotii, to elucidate their real-time chemical communication in commensal harmony. Specifically, we apply nanoscale scanning electrochemical microscopy (SECM) using a submicropipet-supported interface between two immiscible electrolyte solutions as an SECM probe not only to image the permeability of S. mitis and C. matruchotii membranes to tetraethylammonium (TEA+) probe ions but also to real-time visualize the metabolic interaction between two microbes via lactate production/consumption at a single-cell level. The metabolic relationship between two strains is quantitatively assessed by determining (1) the passive permeability of both bacterial membranes of 2.4 × 10-4 cm/s to the free diffusion of TEA+, (2) 0.5 mM of the lactate concentration produced by a single S. mitis strain at a rate of 2.7 × 10-4 cm/s, and (3) a lactate oxidation rate ≥5.0 × 106 s-1 by an individual C. matruchotii strain. Significantly, this study, for the first time, describes a mechanism of in situ metabolic interaction between oral commensals at the single-cell level through quantitative analysis, which supports the observed in vivo spatial arrangements of these microbes.
Asunto(s)
Lactatos , Transducción de Señal , Humanos , Microscopía Electroquímica de Rastreo/métodos , IonesRESUMEN
Squamous Cell Carcinoma (SCC) develops in stratified epithelial tissues and demonstrates frequent alterations in transcriptional regulators. We sought to discover SCC-specific transcriptional programs and identified the transcription factor Basonuclin 1 (BNC1) as highly expressed in SCC compared to other tumor types. RNA-seq and ChIP-seq analysis identified pro-proliferative genes activated by BNC1 in SCC cells and keratinocytes. Inhibition of BNC1 in SCC cells suppressed proliferation and increased migration via FRA1. In contrast, BNC1 reduction in keratinocytes caused differentiation, which was abrogated by IRF6 knockdown, leading to increased migration. Protein interactome analysis identified PRMT1 as a co-activator of BNC1-dependent proliferative genes. Inhibition of PRMT1 resulted in a dose-dependent reduction in SCC cell proliferation without increasing migration. Importantly, therapeutic inhibition of PRMT1 in SCC xenografts significantly reduced tumor size, resembling functional effects of BNC1 knockdown. Together, we identify BNC1-PRMT1 as an SCC-lineage specific transcriptional axis that promotes cancer growth, which can be therapeutically targeted to inhibit SCC tumorigenesis.
RESUMEN
Upper extremity reconstruction may pose clinical challenges for surgeons due to the often-critical, complex functional demands of the damaged and/or missing structures. The advent of vascularized bone grafts (VBGs) has aided in reconstruction of upper extremity (UE) defects due to their superior regenerative properties compared with nonvascularized bone grafts, ability to reconstruct large bony defects, and multiple donor site options. VBGs may be pedicled or free transfers and have the potential for composite tissue transfers when bone and soft tissue are needed. This article provides a comprehensive up-to-date review of VBGs, the commonly reported donor sites, and their indications for the treatment of specific UE defects.
RESUMEN
INTRODUCTION: Clinical options are lacking for the management of chronic wounds or ulcers following failed debridement, skin grafting, or negative pressure wound therapy dressings. OBJECTIVE: This retrospective case series evaluated the efficacy of injectable AAM in the management and closure of chronic wounds. MATERIALS AND METHODS: Patients with nonhealing wounds of any etiology, anatomic location, and length of chronicity were included; those with multiple chronic wounds or prior skin grafting for wound repair were excluded. Data on location, etiology, chronicity, and number of AAM applications were collected for each wound. Patients were evaluated for possible complications related to wound healing and infection. Eleven patients (7 males, 4 females), each with 1 chronic wound, were recruited (average age, 65 years). Wound etiologies were postoperative (n = 7), traumatic (n = 2), and foot ulcer (n = 2). Average wound dimensions were 8.45 mm × 7.36 mm, and the average chronicity was 3.77 months. Ten patients received only 1 application of AAM, and 1 patient received 2 treatments 5 days apart. Average follow-up time was 6.6 weeks. RESULTS: Seven patients (63%) achieved wound closure, 4 of which (57%) healed within 1 week of application. CONCLUSION: Most patients with chronic wounds treated with AAM experienced complete wound closure. AAM shows promising results for enhancing wound healing by providing scaffolding for cell growth.
Asunto(s)
Pie Diabético , Úlcera del Pie , Terapia de Presión Negativa para Heridas , Anciano , Aloinjertos , Pie Diabético/terapia , Femenino , Úlcera del Pie/terapia , Humanos , Masculino , Estudios Retrospectivos , Cicatrización de HeridasRESUMEN
CASE: A 19-year-old woman presented with bilateral mangled upper extremities after jumping in front of a moving train. After revascularization, osteocutaneous free vascularized fibula flap was performed to reconstruct the right humerus. The left forearm required transradial amputation with acute targeted muscle reinnervation. Finally, staged bilateral bipolar latissimus dorsi functional muscle flaps were performed to restore elbow flexion. CONCLUSION: Staged orthoplastic reconstruction of the upper extremities is an effective treatment approach for traumatic bone and soft-tissue defects. This patient's recovery demonstrates improved quality of life after severe upper extremity trauma.