Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates ...migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer.
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•Pipp knockout promotes oncogene-driven breast cancer initiation and growth•Ablation of Pipp impairs metastasis in a mouse model of breast cancer•PIPP regulates AKT1-dependent cell migration and invasion•Low PIPP expression is associated with ER-negative breast cancer and poor prognosis
Ooms et al. identify the inositol polyphosphate 5-phosphatase PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer. PIPP depletion increases transformation and accelerates oncogene-driven tumor growth in vivo, while paradoxically reducing cell migration, invasion, and metastasis.
Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)
) at the plasma membrane in response to growth factors, activating a signalling cascade that ...regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)
facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)
signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)
is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)
), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3
). PtdIns(3,4)
and PtdIns3
are also important signalling molecules; PtdIns(3,4)
together with PtdIns(3,4,5)
are required for maximal AKT activation and PtdIns3
activates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss of
or
expression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)
-mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)
signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes.
How acute pathogens persist and what curtails their epidemic growth in the absence of acquired immunity remains unknown. Canine rabies is a fatal zoonosis that circulates endemically at low ...prevalence among domestic dogs in low- and middle-income countries. We traced rabies transmission in a population of 50,000 dogs in Tanzania from 2002 to 2016 and applied individual-based models to these spatially resolved data to investigate the mechanisms modulating transmission and the scale over which they operate. Although rabies prevalence never exceeded 0.15%, the best-fitting models demonstrated appreciable depletion of susceptible animals that occurred at local scales because of clusters of deaths and dogs already incubating infection. Individual variation in rabid dog behavior facilitated virus dispersal and cocirculation of virus lineages, enabling metapopulation persistence. These mechanisms have important implications for prediction and control of pathogens that circulate in spatially structured populations.
IMPORTANCE: Extracorporeal membrane oxygenation (ECMO) is used as temporary cardiorespiratory support in critically ill patients, but little is known regarding long-term psychiatric sequelae among ...survivors after ECMO. OBJECTIVE: To investigate the association between ECMO survivorship and postdischarge mental health diagnoses among adult survivors of critical illness. DESIGN, SETTING, AND PARTICIPANTS: Population-based retrospective cohort study in Ontario, Canada, from April 1, 2010, through March 31, 2020. Adult patients (N=4462; age ≥18 years) admitted to the intensive care unit (ICU), and surviving to hospital discharge were included. EXPOSURES: Receipt of ECMO. MAIN OUTCOMES AND MEASURES: The primary outcome was a new mental health diagnosis (a composite of mood disorders, anxiety disorders, posttraumatic stress disorder; schizophrenia, other psychotic disorders; other mental health disorders; and social problems) following discharge. There were 8 secondary outcomes including incidence of substance misuse, deliberate self-harm, death by suicide, and individual components of the composite primary outcome. Patients were compared with ICU survivors not receiving ECMO using overlap propensity score–weighted cause-specific proportional hazard models. RESULTS: Among 642 survivors who received ECMO (mean age, 50.7 years; 40.7% female), median length of follow-up was 730 days; among 3820 matched ICU survivors who did not receive ECMO (mean age, 51.0 years; 40.0% female), median length of follow-up was 1390 days. Incidence of new mental health conditions among survivors who received ECMO was 22.1 per 100-person years (95% confidence interval CI 19.5-25.1), and 14.5 per 100-person years (95% CI, 13.8-15.2) among non-ECMO ICU survivors (absolute rate difference of 7.6 per 100-person years 95% CI, 4.7-10.5). Following propensity weighting, ECMO survivorship was significantly associated with an increased risk of new mental health diagnosis (hazard ratio HR 1.24 95% CI, 1.01-1.52). There were no significant differences between survivors who received ECMO vs ICU survivors who did not receive ECMO in substance misuse (1.6 95% CI, 1.1 to 2.4 per 100 person-years vs 1.4 95% CI, 1.2 to 1.6 per 100 person-years; absolute rate difference, 0.2 per 100 person-years 95% CI, −0.4 to 0.8; HR, 0.86 95% CI, 0.48 to 1.53) or deliberate self-harm (0.4 95% CI, 0.2 to 0.9 per 100 person-years vs 0.3 95% CI, 0.2 to 0.3 per 100 person-years; absolute rate difference, 0.1 per 100 person-years 95% CI, −0.2 to 0.4; HR, 0.68 95% CI, 0.21 to 2.23). There were fewer than 5 total cases of death by suicide in the entire cohort. CONCLUSIONS AND RELEVANCE: Among adult survivors of critical illness, receipt of ECMO, compared with ICU hospitalization without ECMO, was significantly associated with a modestly increased risk of new mental health diagnosis or social problem diagnosis after discharge. Further research is necessary to elucidate the potential mechanisms underlying this relationship.
Spatial dynamics of malaria transmission Wu, Sean L; Henry, John M; Citron, Daniel T ...
PLoS computational biology,
06/2023, Letnik:
19, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The Ross-Macdonald model has exerted enormous influence over the study of malaria transmission dynamics and control, but it lacked features to describe parasite dispersal, travel, and other important ...aspects of heterogeneous transmission. Here, we present a patch-based differential equation modeling framework that extends the Ross-Macdonald model with sufficient skill and complexity to support planning, monitoring and evaluation for Plasmodium falciparum malaria control. We designed a generic interface for building structured, spatial models of malaria transmission based on a new algorithm for mosquito blood feeding. We developed new algorithms to simulate adult mosquito demography, dispersal, and egg laying in response to resource availability. The core dynamical components describing mosquito ecology and malaria transmission were decomposed, redesigned and reassembled into a modular framework. Structural elements in the framework-human population strata, patches, and aquatic habitats-interact through a flexible design that facilitates construction of ensembles of models with scalable complexity to support robust analytics for malaria policy and adaptive malaria control. We propose updated definitions for the human biting rate and entomological inoculation rates. We present new formulas to describe parasite dispersal and spatial dynamics under steady state conditions, including the human biting rates, parasite dispersal, the "vectorial capacity matrix," a human transmitting capacity distribution matrix, and threshold conditions. An Formula: see text package that implements the framework, solves the differential equations, and computes spatial metrics for models developed in this framework has been developed. Development of the model and metrics have focused on malaria, but since the framework is modular, the same ideas and software can be applied to other mosquito-borne pathogen systems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the role of different species in the transmission of multi‐host pathogens, such as rabies virus, is vital for effective control strategies. Across most of sub‐Saharan Africa domestic ...dogs Canis familiaris are considered the reservoir for rabies, but the role of wildlife has been long debated. Here we explore the multi‐host transmission dynamics of rabies across south‐east Tanzania.
Between January 2011 and July 2019, data on probable rabies cases were collected in the regions of Lindi and Mtwara. Hospital records of animal‐bite patients presenting to healthcare facilities were used as sentinels for animal contact tracing. The timing, location and species of probable rabid animals were used to reconstruct transmission trees to infer who infected whom and the relative frequencies of within‐ and between‐species transmission.
During the study, 688 probable human rabies exposures were identified, resulting in 47 deaths. Of these exposures, 389 were from domestic dogs (56.5%) and 262 from jackals (38.1%). Over the same period, 549 probable animal rabies cases were traced: 303 in domestic dogs (55.2%) and 221 in jackals (40.3%), with the remainder in domestic cats and other wildlife species.
Although dog‐to‐dog transmission was most commonly inferred (40.5% of transmission events), a third of inferred events involved wildlife‐to‐wildlife transmission (32.6%), and evidence suggested some sustained transmission chains within jackal populations.
A steady decline in probable rabies cases in both humans and animals coincided with the implementation of widespread domestic dog vaccination during the first 6 years of the study. Following the lapse of this program, dog rabies cases began to increase in one of the northernmost districts.
Synthesis and applications. In south‐east Tanzania, despite a relatively high incidence of rabies in wildlife and evidence of wildlife‐to‐wildlife transmission, domestic dogs remain essential to the reservoir of infection. Continued dog vaccination alongside improved surveillance would allow a fuller understanding of the role of wildlife in maintaining transmission in this area. Nonetheless, dog vaccination clearly suppressed rabies in both domestic dog and wildlife populations, reducing both public health and conservation risks and, if sustained, has potential to eliminate rabies from this region.
In south‐east Tanzania, despite a relatively high incidence of rabies in wildlife and evidence of wildlife‐to‐wildlife transmission, domestic dogs remain essential to the reservoir of infection. Continued dog vaccination alongside improved surveillance would allow a fuller understanding of the role of wildlife in maintaining transmission in this area. Nonetheless, dog vaccination clearly suppressed rabies in both domestic dog and wildlife populations, reducing both public health and conservation risks and, if sustained, has potential to eliminate rabies from this region.
Katie Hampson and colleagues describe their experience of developing and deploying a large-scale rabies surveillance system based on mobile phones in southern Tanzania.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients surviving an ICU admission for deliberate self-harm are at high risk of recurrent self-harm or suicide after discharge. It is unknown whether mental health follow-up after discharge (with ...either a family physician or psychiatrist) reduces this risk.
What is the association between mental health follow-up after discharge and recurrent self-harm among patients admitted to the ICU for intentional self-harm?
Population-based cohort study of consecutive adults (≥ 18 years of age) from Ontario, Canada, who were admitted to ICU because of intentional self-harm between 2009 and 2017. We categorized patients according to follow-up, with 'early follow-up' indicating 1 to 21 days after discharge, 'late follow-up' indicating 22 to 60 days after discharge, and 'no follow-up' indicating no follow-up within 60 days of discharge. We conducted analyses using a cause-specific extended Cox regression model to account for varying time for mental health follow-up relative to the outcomes of interest. The primary outcome was recurrent ICU admission for self-harm within 1 year of discharge.
We included 9,569 consecutive adults admitted to the ICU for deliberate self-harm. Compared with receiving no mental health follow-up, both early follow-up (hazard ratio HR, 1.37; 95% CI, 1.07-1.75) and late follow-up (HR, 1.69; 95% CI, 1.22-2.35) were associated with increased risk in recurrent ICU admission for self-harm. As compared with no follow-up, neither early follow-up (HR, 1.10; 95% CI, 0.70-1.73) nor late follow-up (HR, 1.54; 95% CI, 0.84-2.83) were associated with increased risk of death by suicide.
Among adults admitted to the ICU for deliberate self-harm, mental health follow-up after discharge was not associated with reduced risk of recurrent ICU admission for self-harm or death resulting from suicide, and patients seeking outpatient follow-up may be those at highest risk of these outcomes. Future research should focus on additional and novel methods of risk mitigation in this vulnerable population.
PURPOSEWe aimed to measure 1) the dynamics of locomotor fatigue during constant supra-critical power cycling and 2) the magnitude of any reserve in locomotor power at intolerance to constant and ...ramp-incremental cycling in recreationally active volunteers.
METHODSFifteen participants (7 women and 8 men, 22 ± 3 yr, 3.34 ± 0.67 L·min V˙O2peak) completed ramp-incremental and very-heavy constant power (205 ± 46 W) exercise to the limit of tolerance. Immediately after intolerance, the ergometer was switched into the isokinetic mode, and participants completed a short (~5 s) maximal isokinetic effort at 70 rpm. The time course of locomotor fatigue during constant supra-critical power exercise was characterized with these short maximal isokinetic sprints at 30, 60, 120, and 180 s and at the limit of tolerance. Each bout was terminated after the isokinetic sprint.
RESULTSConstant power exercise duration was 312 ± 37 s. Isokinetic power production values at 30, 60, 120, and 180 s and at the limit of tolerance (at 312 ± 37 s) was 609 ± 165, 503 ± 195, 443 ± 157, 449 ± 133, and 337 ± 94 W, respectively. Of the total decline in isokinetic power, ~36% occurred within the first minute of exercise, and significant (P < 0.05) reductions in isokinetic power occurred at all time points versus the baseline maximal isokinetic power (666 ± 158 W). In addition, a significant power reserve of 132 ± 74 W (64% of the task requirement) and 119 ± 80 W (47%) was present at the limit of constant power and ramp-incremental exercise, respectively.
CONCLUSIONSLocomotor fatigue occurred rapidly during supracritical power exercise with pseudo-exponential kinetics. Instantaneous isokinetic power production at the limit of tolerance exceeded that of the task requirement, regardless of the constant or ramp work rate profile. Thus, the perceptual and physiologic limits were dissociated at the limit of tolerance in recreationally active volunteers.
Understanding the factors influencing vaccination campaign effectiveness is vital in designing efficient disease elimination programmes. We investigated the importance of spatial heterogeneity in ...vaccination coverage and human-mediated dog movements for the elimination of endemic canine rabies by mass dog vaccination in Region VI of the Philippines (Western Visayas). Household survey data was used to parameterise a spatially-explicit rabies transmission model with realistic dog movement and vaccination coverage scenarios, assuming a basic reproduction number for rabies drawn from the literature. This showed that heterogeneous vaccination reduces elimination prospects relative to homogeneous vaccination at the same overall level. Had the three vaccination campaigns completed in Region VI in 2010-2012 been homogeneous, they would have eliminated rabies with high probability. However, given the observed heterogeneity, three further campaigns may be required to achieve elimination with probability 0.95. We recommend that heterogeneity be reduced in future campaigns through targeted efforts in low coverage areas, even at the expense of reduced coverage in previously high coverage areas. Reported human-mediated dog movements did not reduce elimination probability, so expending limited resources on restricting dog movements is unnecessary in this endemic setting. Enhanced surveillance will be necessary post-elimination, however, given the reintroduction risk from long-distance dog movements.
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