RESUMEN
Importance: Obesity, especially visceral obesity, is an established risk factor associated with all-cause mortality. However, the inadequacy of conventional anthropometric measures in assessing fat distribution necessitates a more comprehensive indicator, body roundness index (BRI), to decipher its population-based characteristics and potential association with mortality risk. Objective: To evaluate the temporal trends of BRI among US noninstitutionalized civilian residents and explore its association with all-cause mortality. Design, Setting, and Participants: For this cohort study, information on a nationally representative cohort of 32â¯995 US adults (age ≥20 years) was extracted from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and NHANES Linked Mortality File, with mortality ascertained through December 31, 2019. Data were analyzed between April 1 and September 30, 2023. Exposures: Biennial weighted percentage changes in BRI were calculated. Restricted cubic spline curve was used to determine optimal cutoff points for BRI. Main Outcome and Measures: The survival outcome was all-cause mortality. Mortality data were obtained from the Centers for Disease Control and Prevention website and linked to the NHANES database using the unique subject identifier. Weibull regression model was adopted to quantify the association between BRI and all-cause mortality. Results: Among 32â¯995 US adults, the mean (SD) age was 46.74 (16.92) years, and 16â¯529 (50.10%) were women. Mean BRI increased gradually from 4.80 (95% CI, 4.62-4.97) to 5.62 (95% CI, 5.37-5.86) from 1999 through 2018, with a biennial change of 0.95% (95% CI, 0.80%-1.09%; P < .001), and this increasing trend was more obvious among women, elderly individuals, and individuals who identified as Mexican American. After a median (IQR) follow-up of 9.98 (5.33-14.33) years, 3452 deaths (10.46% of participants) from all causes occurred. There was a U-shaped association between BRI and all-cause mortality, with the risk increased by 25% (hazard ratio, 1.25; 95% CI, 1.05-1.47) for adults with BRI less than 3.4 and by 49% (hazard ratio, 1.49; 95% CI, 1.31-1.70) for those with BRI of 6.9 or greater compared with the middle quintile of BRI of 4.5 to 5.5 after full adjustment. Conclusions and Relevance: This national cohort study found an increasing trend of BRI during nearly 20-year period among US adults, and importantly, a U-shaped association between BRI and all-cause mortality. These findings provide evidence for proposing BRI as a noninvasive screening tool for mortality risk estimation, an innovative concept that could be incorporated into public health practice pending consistent validation in other independent cohorts.
Asunto(s)
Encuestas Nutricionales , Humanos , Femenino , Masculino , Adulto , Estados Unidos/epidemiología , Persona de Mediana Edad , Mortalidad/tendencias , Estudios de Cohortes , Anciano , Causas de Muerte/tendencias , Factores de Riesgo , Índice de Masa Corporal , Obesidad/mortalidad , Obesidad/epidemiología , Adulto JovenRESUMEN
Despite identifying El Niño events as a factor in dengue dynamics, predicting the oscillation of global dengue epidemics remains challenging. Here, we investigate climate indicators and worldwide dengue incidence from 1990 to 2019 using climate-driven mechanistic models. We identify a distinct indicator, the Indian Ocean basin-wide (IOBW) index, as representing the regional average of sea surface temperature anomalies in the tropical Indian Ocean. IOBW is closely associated with dengue epidemics for both the Northern and Southern hemispheres. The ability of IOBW to predict dengue incidence likely arises as a result of its effect on local temperature anomalies through teleconnections. These findings indicate that the IOBW index can potentially enhance the lead time for dengue forecasts, leading to better-planned and more impactful outbreak responses.
Asunto(s)
Dengue , Epidemias , Humanos , Modelos Climáticos , Dengue/epidemiología , El Niño Oscilación del Sur , Incidencia , Océano Índico , CalorRESUMEN
Continually emerging SARS-CoV-2 variants of concern that can evade immune defenses are driving recurrent epidemic waves of COVID-19 globally. However, the impact of measures to contain the virus and their effect on lineage diversity dynamics are poorly understood. Here, we jointly analyzed international travel, public health and social measures (PHSM), COVID-19 vaccine rollout, SARS-CoV-2 lineage diversity, and the case growth rate (GR) from March 2020 to September 2022 across 63 countries. We showed that despite worldwide vaccine rollout, PHSM are effective in mitigating epidemic waves and lineage diversity. An increase of 10,000 monthly travelers in a single country-to-country route between endemic countries corresponds to a 5.5% (95% CI: 2.9 to 8.2%) rise in local lineage diversity. After accounting for PHSM, natural immunity from previous infections, and waning immunity, we discovered a negative association between the GR of cases and adjusted vaccine coverage (AVC). We also observed a complex relationship between lineage diversity and vaccine rollout. Specifically, we found a significant negative association between lineage diversity and AVC at both low and high levels but not significant at the medium level. Our study deepens the understanding of population immunity and lineage dynamics for future pandemic preparedness and responsiveness.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Vacunas contra la COVID-19 , Salud Pública , COVID-19/epidemiología , COVID-19/prevención & control , Vacunación , Pandemias/prevención & controlRESUMEN
Triple negative breast cancer (TNBC) is more aggressive and has a poorer prognosis than other sub-types of breast tumors. This study elucidates how aspartate beta-hydroxylase (ASPH) network promotes drug resistance, and immunotherapy targeting ASPH may improve the efficacy of Doxorubicin (DOX) therapy. An orthotopic model of breast cancer generated by 4T1 cells in immunocompetent mice was used to explore efficacy of immunotherapy in combination with DOX chemotherapy. We evaluated mRNA and protein expression in cultured tumor cells and tissue, as well as assessed cell proliferation, apoptosis, soluble factors/cytokine production, immune cell population diversity and function. We observed that ASPH expression enables TNBC cells to exhibit primary resistance to DOX induced single-/double-strand breaks (SSB/DSB) and enhanced proliferation and survival. Specific bio-nanoparticle based therapeutic vaccine (BNP-TV) promoted ASPH uptake by and maturation of DCs. This BNP-TV combined with DOX induces immunogenic cell death (ICD) in orthotopic xenograft tumors and significantly suppressed primary mammary tumor growth and distant multi-organ metastases. Immunogenic cell death induced by BNP-TV targeting ASPH combined with DOX provides opportunities to treat a highly resistant and metastatic form of breast cancer.
RESUMEN
A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.
RESUMEN
To avoid possible confusions to the readers, we provide further explanations for the eq. (3) in the research article "Estimating the daily trend in the size of the COVID-19 infected population in Wuhan" published in the Infectious Diseases of Poverty.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Neumonía Viral/epidemiología , Neumonía Viral/virología , Betacoronavirus/aislamiento & purificación , COVID-19 , China/epidemiología , Humanos , Modelos Estadísticos , Pandemias , SARS-CoV-2RESUMEN
We have proposed a novel, accurate low-cost method to estimate the incubation-period distribution of COVID-19 by conducting a cross-sectional and forward follow-up study. We identified those presymptomatic individuals at their time of departure from Wuhan and followed them until the development of symptoms. The renewal process was adopted by considering the incubation period as a renewal and the duration between departure and symptoms onset as a forward time. Such a method enhances the accuracy of estimation by reducing recall bias and using the readily available data. The estimated median incubation period was 7.76 days [95% confidence interval (CI): 7.02 to 8.53], and the 90th percentile was 14.28 days (95% CI: 13.64 to 14.90). By including the possibility that a small portion of patients may contract the disease on their way out of Wuhan, the estimated probability that the incubation period is longer than 14 days was between 5 and 10%.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Periodo de Incubación de Enfermedades Infecciosas , Modelos Estadísticos , Neumonía Viral/epidemiología , Neumonía Viral/transmisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Niño , Preescolar , China/epidemiología , Infecciones por Coronavirus/virología , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Adulto JovenRESUMEN
BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19) has quickly spread across countries and become a global crisis. However, one of the most important clinical characteristics in epidemiology, the distribution of the incubation period, remains unclear. Different estimates of the incubation period of COVID-19 were reported in recent published studies, but all have their own limitations. In this study, we propose a novel low-cost and accurate method to estimate the incubation distribution. METHODS: We have conducted a cross-sectional and forward follow-up study by identifying those asymptomatic individuals at their time of departure from Wuhan and then following them until their symptoms developed. The renewal process is hence adopted by considering the incubation period as a renewal and the duration between departure and symptom onset as a forward recurrence time. Under mild assumptions, the observations of selected forward times can be used to consistently estimate the parameters in the distribution of the incubation period. Such a method enhances the accuracy of estimation by reducing recall bias and utilizing the abundant and readily available forward time data. FINDINGS: The estimated distribution of forward time fits the observations in the collected data well. The estimated median of incubation period is 8·13 days (95% confidence interval [CI]: 7·37-8·91), the mean is 8·62 days (95% CI: 8·02-9·28), the 90th percentile is 14·65 days (95% CI: 14·00-15·26), and the 99th percentile is 20·59 days (95% CI: 19·47, 21·62). Compared with results in other studies, the incubation period estimated in this study is longer. INTERPRETATION: Based on the estimated incubation distribution in this study, about 10% of patients with COVID-19 would not develop symptoms until 14 days after infection. Further study of the incubation distribution is warranted to directly estimate the proportion with long incubation periods.
RESUMEN
BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has become a pandemic causing global health problem. We provide estimates of the daily trend in the size of the epidemic in Wuhan based on detailed information of 10 940 confirmed cases outside Hubei province. METHODS: In this modelling study, we first estimate the epidemic size in Wuhan from 10 January to 5 April 2020 with a newly proposed model, based on the confirmed cases outside Hubei province that left Wuhan by 23 January 2020 retrieved from official websites of provincial and municipal health commissions. Since some confirmed cases have no information on whether they visited Wuhan before, we adjust for these missing values. We then calculate the reporting rate in Wuhan from 20 January to 5 April 2020. Finally, we estimate the date when the first infected case occurred in Wuhan. RESULTS: We estimate the number of cases that should be reported in Wuhan by 10 January 2020, as 3229 (95% confidence interval [CI]: 3139-3321) and 51 273 (95% CI: 49 844-52 734) by 5 April 2020. The reporting rate has grown rapidly from 1.5% (95% CI: 1.5-1.6%) on 20 January 2020, to 39.1% (95% CI: 38.0-40.2%) on 11 February 2020, and increased to 71.4% (95% CI: 69.4-73.4%) on 13 February 2020, and reaches 97.6% (95% CI: 94.8-100.3%) on 5 April 2020. The date of first infection is estimated as 30 November 2019. CONCLUSIONS: In the early stage of COVID-19 outbreak, the testing capacity of Wuhan was insufficient. Clinical diagnosis could be a good complement to the method of confirmation at that time. The reporting rate is very close to 100% now and there are very few cases since 17 March 2020, which might suggest that Wuhan is able to accommodate all patients and the epidemic has been controlled.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Métodos Epidemiológicos , Modelos Estadísticos , Neumonía Viral/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Niño , Preescolar , China/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Adulto JovenRESUMEN
BACKGROUND: The 2019 novel coronavirus (COVID-19) outbreak in Wuhan, China has attracted world-wide attention. As of March 31, 2020, a total of 82,631 cases of COVID-19 in China were confirmed by the National Health Commission (NHC) of China. METHODS: Three approaches, namely Poisson likelihood-based method (ML), exponential growth rate-based method (EGR) and stochastic Susceptible-Infected-Removed dynamic model-based method (SIR), were implemented to estimate the basic and controlled reproduction numbers. RESULTS: A total of 198 chains of transmission together with dates of symptoms onset and 139 dates of infections were identified among 14,829 confirmed cases outside Hubei Province as reported as of March 31, 2020. Based on this information, we found that the serial interval had an average of 4.60 days with a standard deviation of 5.55 days, the incubation period had an average of 8.00 days with a standard deviation of 4.75 days and the infectious period had an average of 13.96 days with a standard deviation of 5.20 days. The estimated controlled reproduction numbers, Rc, produced by all three methods in all analyzed regions of China are significantly smaller compared with the basic reproduction numbers R0. CONCLUSIONS: The controlled reproduction number in China is much lower than one in all regions of China by now. It fell below one within 30 days from the implementations of unprecedent containment measures, which indicates that the strong measures taken by China government was effective to contain the epidemic. Nonetheless, efforts are still needed in order to end the current epidemic as imported cases from overseas pose a high risk of a second outbreak.
Asunto(s)
Número Básico de Reproducción/estadística & datos numéricos , Betacoronavirus , Infecciones por Coronavirus/epidemiología , Brotes de Enfermedades/estadística & datos numéricos , Modelos Estadísticos , Neumonía Viral/epidemiología , COVID-19 , China/epidemiología , Infecciones por Coronavirus/virología , Humanos , Pandemias , Neumonía Viral/virología , SARS-CoV-2RESUMEN
To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.
Asunto(s)
Exosomas/patología , Neoplasias Pulmonares/patología , Neoplasias Pancreáticas/patología , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Pronóstico , Transducción de Señal/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Neoplasias PancreáticasRESUMEN
We investigated the epidemiological and clinical characteristics deaths from road traffic injury (RTI) in Beijing, and provided evidence useful for the prevention of fatal traffic trauma and for the treatment of traffic-related injuries.We retrospectively reviewed death cases provided by the Beijing Red Cross Emergency Center on road traffic injury deaths from 2008 to 2017. We analyzed population characteristics, time distribution, distribution of transportation modes, intervals to death, locations and injured body parts.From 2008 to 2017, there were 3327 deaths from RTI recorded by the Beijing Red Cross Emergency Center, with mainly males among these deaths. The average age at death was 46.19â±â17.43 years old (46.19, 0.43-100.24). In accidents with more detail recorded, pedestrians and people using nonmotorized transportation modes suffered the most fatalities (664/968, 68.60%). The most commonly injured body parts were the head (2569/3327, 77.22%), followed by the chest (180/3327, 5.41%), abdomen (130/3327, 3.91%), lower extremities (68/3327, 2.04%), pelvis (67/3327, 2.01%), spinal cord (31/3327, 0.93%), and upper extremities (26/3327, 0.78%). Burns accounted for 0.96% (32/3327), and unknown body parts were affected in 11.28% (365/3327). The average time interval from injury to death was 36.90â±â89.57âh (36.90, 0-720); 46.7% (1554/3327) died within 10âminutes after injury; 9.02% (300/3327) died between 10âmin and 1 hour; 30.33% (1009/3327) died between 1 hour and 3 days; 13.95% (464/3327) died between 3 and 30 days.In Beijing, RTI is a significant cause of preventable death, particularly among pedestrians and users of non-motorized vehicles. Head trauma was the most lethal cause of RTI deaths. Our findings suggested that interventions to prevent collisions and reduce injuries, and improved trauma treatment process and trauma rescue system could address a certain proportion of avoidable RTI deaths.
Asunto(s)
Accidentes de Tránsito/mortalidad , Traumatismos Craneocerebrales/mortalidad , Peatones/estadística & datos numéricos , Heridas y Lesiones/mortalidad , Adulto , Anciano , Beijing/epidemiología , Traumatismos Craneocerebrales/etiología , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Centros Traumatológicos/estadística & datos numéricos , Heridas y Lesiones/etiologíaRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.2840.].
RESUMEN
BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas de Unión al Calcio/metabolismo , Exosomas/metabolismo , Proteínas de la Membrana/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas Musculares/metabolismo , Proteoma , Receptores Notch/metabolismo , Animales , Biomarcadores , Comunicación Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Femenino , Genes Reporteros , Xenoinjertos , Humanos , Inmunohistoquímica , Ligandos , Metaloproteinasas de la Matriz/metabolismo , Ratones , Modelos Biológicos , Metástasis de la Neoplasia , Fenotipo , Transducción de SeñalRESUMEN
INTRODUCTION: Acellular dermal matrix (ADM) is a common filler used widely in clinical practice to increase penile girth for cosmetic reasons, but there are few studies on its complications. AIM: The aim of this study was to investigate and analyze the complications of penile girth enhancement (PGE) with ADM. METHODS: The medical records of 78 patients who underwent PGE with ADM between June 2016 and January 2019 were retrospectively reviewed. MAIN OUTCOME MEASURE: Related complications and their subsequent management were summarized and analyzed. RESULTS: 78 patients (mean age 31.14 years [21-66 years]) received PGE with ADM. At the 3-month follow-up, the penile circumference was increased by 1.1 (0.5-2.1) cm on average. There were 47 patients with erectile discomfort, 12 with delayed healing, 10 with unobvious augmentation effect, 8 with wound hematoma, 7 with prepuce edema, 4 with wound infection, and 3 patients with skin necrosis of the dorsal side. 7 patients eventually underwent ADM removal. CLINICAL IMPLICATIONS: These adverse complications indicate that ADM should be used with caution for PGE. STRENGTH & LIMITATIONS: This study adds important data, as there are few published reports on the complications of PGE with ADM. However, this study did not compare postoperative complications with ADM to those seen with other filler material. CONCLUSION: Even with standardized surgical methods and rigorous postoperative care, complications of PGE using ADM are severe, which indicates that it is not an ideal or safe method for PGE. Xu T, Zhang G, Bai W, et al. Complications and Management of Penile Girth Enhancement with Acellular Dermal Matrix. J Sex Med 2019;16:2011-2017.
Asunto(s)
Dermis Acelular/efectos adversos , Enfermedades del Pene/etiología , Pene/cirugía , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Erección Peniana , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate ß-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's ß-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/metabolismo , Carcinoma Ductal Pancreático/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/secundario , Proteínas de la Membrana/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas Musculares/metabolismo , Neoplasias Pancreáticas/patología , Familia-src Quinasas/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proteínas de Unión al Calcio/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Oxigenasas de Función Mixta/genética , Proteínas Musculares/genética , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pronóstico , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/genéticaRESUMEN
Portal vein hypertension (PVH) in liver cirrhosis complicated with portal venous thrombosis (PVT) has been mainly treated with transjugular intrahepatic portosystemic shunt (TIPS). The clinical effects of TIPS have been confirmed, however, no large-scale studies have been focused on technical analyses and a long-term follow-up, especially on thrombotic total occlusion of main portal vein (MPV). To demonstrate critical techniques and clinical outcome of TIPS on liver cirrhosis-related thrombotic total occlusion of MPV, 98 patients diagnosed with liver cirrhosis related thrombotic total occlusion of MPV and treated with TIPS from January 2000 to January 2010 were retrospectively analyzed. Twenty-three (23.5%) patients had MPV (single site) thrombosis, 55 (56.1%) had multiple site-thrombosis (MPV and other), 17 (17.3%) had cavernous transformation of portal vein, and 3 (3.1%) had post-transplant thrombosis. The successful rate of TIPS was 90.7%, without any procedure-related deaths or severe complications. Mean portal pressure was dropped from 33.08 ± 1.38 mmHg preoperatively to 20.18 ± 0.83 mmHg postoperatively (p < 0.001). Collectively, TIPS is safe and effective in treating liver cirrhosis-related thrombotic total occlusion of MPV. This complex procedure requires combination of indirect portography and percutaneous transhepatic portal techniques to increase the rate of success.