Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the ...lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.
The COVID-19 pandemic had a major global impact on the health and wellbeing for many individuals. Even though the infection rates have gone down due to the availability of vaccines, the consequences ...of the disease are still present due to persistent symptoms among individuals. The aim of the current study was to map long-term impairments in individuals infected with COVID-19 by applying the framework of the World Health Organization's International Classification of Functioning, Disability and Health (ICF) and also investigate the factors related to the context of an individual's life influencing the impairments. A web-survey that targeted individuals that had been infected with COVID-19 was used. The survey included a range of measures covering contextual factors and factors related to body functions and structures and post-COVID impairments. A total of 501 individuals were included in the study (with a mean age of 47.6 years). 96% of the respondents reported at least one moderate-to-severe impairment due to COVID-19 infection and the most frequent one was fatigue. In that, 79.6% and 86.9% of the study sample reported moderate-to-severe brain fatigue and tiredness or lack of energy, respectively. Severity of COVID-19 infection appeared as the strongest risk factor for post-COVID impairments. Based on the results, interventions can be tailored to help individuals with post-COVID-19 condition. This could be one way lessening the effect of COVID-19 on health care and society as a whole.
GaAsBi nanowires represent a novel and promising material platform for future nano-photonics. However, the growth of high-quality GaAsBi nanowires and GaAsBi alloy is still a challenge due to a large ...miscibility gap between GaAs and GaBi. In this work we investigate effects of Bi incorporation on lattice dynamics and carrier recombination processes in GaAs/GaAsBi core/shell nanowires grown by molecular-beam epitaxy. By employing photoluminescence (PL), PL excitation, and Raman scattering spectroscopies complemented by scanning electron microscopy, we show that increasing Bi-beam equivalent pressure (BEP) during the growth does not necessarily result in a higher alloy composition but largely affects the carrier localization in GaAsBi. Specifically, it is found that under high BEP, bismuth tends either to be expelled from a nanowire shell towards its surface or to form larger clusters within the GaAsBi shell. Due to these two processes the bandgap of the Bi-containing shell remains practically independent of the Bi BEP, while the emission spectra of the NWs experience a significant red shift under increased Bi supply as a result of the localization effect.
Parvalbumin (PV) interneurons are inhibitory fast-spiking cells with essential roles in directing the flow of information through cortical circuits. These neurons set the balance between excitation ...and inhibition and control rhythmic activity. PV interneurons differ between cortical layers in their morphology, circuitry, and function, but how their electrophysiological properties vary has received little attention. Here we investigate responses of PV interneurons in different layers of primary somatosensory barrel cortex (BC) to different excitatory inputs. With the genetically-encoded hybrid voltage sensor, hVOS, we recorded voltage changes in many L2/3 and L4 PV interneurons simultaneously, with stimulation applied to either L2/3 or L4. A semi-automated procedure was developed to identify small regions of interest corresponding to single responsive PV interneurons. Amplitude, half-width, and rise-time were greater for PV interneurons residing in L2/3 compared to L4. Stimulation in L2/3 elicited responses in both L2/3 and L4 with longer latency compared to stimulation in L4. These differences in latency between layers could influence their windows for temporal integration. Thus, PV interneurons in different cortical layers of BC respond in a layer specific and input specific manner, and these differences have potential roles in cortical computations.
During breast cancer progression, transforming growth factor-beta (TGF-β) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion ...and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPβ), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-β-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBPβ was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBPβ potentiated the TGF-β response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-β. Furthermore, loss of C/EBPβ enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBPβ promoted the TGF-β response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBPβ as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBPβ as a mechanism, which promotes breast cancer progression by shifting the TGF-β response from growth inhibition to EMT, invasion and metastasis.
•Qualitative analysis of motivators and barriers to SUD treatment during pregnancy.•Motivators: Custody, baby’s health, daily structure / housing, ready to stop using.•Hesitation/ barriers: Custody ...concern, stigma, lack of transportation or childcare.•Identifying barriers and motivators may guide work to improve access to treatment.
Pregnancy is a unique opportunity to provide broad and necessary medical care for women- including treatment for Substance Use Disorders (SUD). The standard of care for SUD in pregnant women is treatment at a comprehensive care facility. There is little existing qualitative research exploring what brings pregnant women with SUD to treatment and what barriers to treatment exist for this population. This study explored women's self-reported reasons for pursuing treatment or hesitating to do so.
This qualitative study used interviews to explore common factors that motivate pregnant women with SUD to seek comprehensive care during pregnancy and common hesitations/ barriers to treatment. The study population included 20 women in treatment at a comprehensive care facility for pregnant and parenting women at Johns Hopkins. Participants volunteered to do interviews which were recorded and transcribed for analysis.
Interviews revealed several major themes in motivators to seek treatment: readiness to stop using, concern for the baby's health, concern about custody of the baby or other children, wanting to escape violent environments or homelessness, and seeking structure. Barriers to treatment included fear of loss of custody, not wanting to be away from children/partner, concern about stigma or privacy, and lack of childcare and transportation.
This study revealed common motivators to seek treatment and barriers to treatment for pregnant women with SUD. These themes may help direct future studies and guide efforts to increase access to crucial care in this vulnerable population.
We report on optimization of growth conditions of GaAs/GaNAs/GaAs core/shell/shell nanowire (NW) structures emitting at ∼1 m, aiming to increase their light emitting efficiency. A slight change in ...growth temperature is found to critically affect optical quality of the active GaNAs shell and is shown to result from suppressed formation of non-radiative recombination (NRR) centers under the optimum growth temperature. By employing the optically detected magnetic resonance spectroscopy, we identify gallium vacancies and gallium interstitials as being among the dominant NRR defects. The radiative efficiency of the NWs can be further improved by post-growth annealing at 680 °C, which removes the gallium interstitials.
MicroRNAs (miRNAs) regulate many key cancer-relevant pathways and may themselves possess oncogenic or tumor-suppressor functions. Consequently, miRNA dysregulation has been shown to be a prominent ...feature in many human cancers. The p53 tumor suppressor acts as a negative regulator of cell proliferation in response to stress and represents the most commonly lost and mutated gene in human cancers. The function of p53 is inhibited by the MDM2 oncoprotein. Using a high-throughput screening approach, we identified miR-339-5p as a regulator of the p53 pathway. We demonstrate that this regulation occurs via the ability of miR-339-5p to target directly the 3'-untranslated region of MDM2 mRNA, reducing MDM2 expression and thus promoting p53 function. Consequently, overexpression of miR-339-5p positively impacts on p53-governed cellular responses such as proliferation arrest and senescence, whereas inhibition of miR-339-5p function perturbs the p53 response in cancer cells, allowing an increased proliferation rate. In addition, miR-339-5p expression is downregulated in tumors harboring wild-type TP53, suggesting that reduction of miR-339-5p level helps to suppress the p53 response in p53-competent tumor cells. Furthermore, we show that a negative correlation between miR-339-5p and MDM2 expression exists in human cancer, implying that the interaction is important for cancer development.
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