Our understanding of the evolution, formation, and pathological disruption of human brain circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. A whole-genome, ...exon-level expression analysis of 13 regions from left and right sides of the mid-fetal human brain revealed that 76% of genes are expressed, and 44% of these are differentially regulated. These data reveal a large number of specific gene expression and alternative splicing patterns, as well as coexpression networks, associated with distinct regions and neurodevelopmental processes. Of particular relevance to cognitive specializations, we have characterized the transcriptional landscapes of prefrontal cortex and perisylvian speech and language areas, which exhibit a population-level global expression symmetry. We show that differentially expressed genes are more frequently associated with human-specific evolution of putative
cis-regulatory elements. These data provide a wealth of biological insights into the complex transcriptional and molecular underpinnings of human brain development and evolution.
The problem of unemployment is one of the key questions of every modern economy and one of the most important indicators of its efficiency. A higher level of entrepreneurial interest and activities ...can be an important part of economic growth. However, most citizens, especially young people, are more oriented towards finding work in existing companies than starting their own business. Therefore, the primary goal of the research is better understanding of the interests of senior students at universities in Serbia, in terms of entrepreneurial careers and identifying the key factors that influence them. The study is based on a modification of social cognitive theory model, focusing primarily on the interests and goals of students in terms of entrepreneurship.
DOG1, a Ca2+-activated Cl− channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, ...but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl− currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.
•Subcellular DOG1 localization varies between GIST cells.•DOG1 in GIST is voltage- and Ca2+-activated.•Known TMEM16A modulators, like A01 and Eact, modulate DOG1.•DOG1 has small effects on cell viability and proliferation in vitro.•DOG1 impact early apoptotic GIST cells to undergo late apoptosis.
BACKGROUND.Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated ...rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact.
METHODS.We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome.
RESULTS.Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge.
CONCLUSIONS.While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
Metachronous CRCLM should be evaluated by multidisciplinary oncologic consilium. Diagnostic evaluation must be completed by dinamic CT or MR of the liver. In the case of a small number of metastases, ...operation could be performed immediately. In such cases, neoadjuvant therapy could be recomended because of decreasing recurrence rates, slight increase of the overall survival rate and to evaluate malignant potential. Neoadjuvant therapy is mandatory in cases with >4 metastases and potentialy resectable metastases, due to possibility to convert 25% of them to secondary resectable category. In the case of incidentaly discovered metastases (during the primary colorectal operation), the removal of primary tumor should not be abandoned. Biopsy of metastatic lesion is not recomended. Complications of CRC should be treated by palliative procedures /stoma, palliative resection, interventional endoscopy or radiology) followed by consiliary multidisciplinary teratment and liver surgery in the second operative act. Asymptomatic T 1,2, N 0,1 primary tumors of the right colon could be treated by simultaneous major liver resection. Left colonic and rectal resection could be safe combined with minor liver resection (up to 2 liver segments). In the cases of T 3,4, N 1,2 CRC with synchronous liver metastases neoadjuvant therapy is mandatory, as in the cases of multiple (>4) metastases. Reverse strategy could be effective in these cases.
DOG1, a Ca{sup 2+}-activated Cl{sup −} channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine ...diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl{sup −} currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target. - Highlights: • Subcellular DOG1 localization varies between GIST cells. • DOG1 in GIST is voltage- and Ca{sup 2+}-activated. • Known TMEM16A modulators, like A01 and Eact, modulate DOG1. • DOG1 has small effects on cell viability and proliferation in vitro. • DOG1 impact early apoptotic GIST cells to undergo late apoptosis.
Introduction: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition associated with fibroinflammatory lesions that can occur at almost any anatomical site. It often presents as ...a multiorgan disease that may mimic malignancy, infection, or other immune-mediated conditions. Autoimmune pancreatitis (AIP) type 1 is the most prominent manifestation of IgG4-RD in the digestive tract, with common extra-pancreatic inflammation. We present the first patient with AIP and involvement of the testicles and nasal cavity. Patient and methods: A case of a patient with AIP type 1 and other organ involvement (bile ducts, testicles, nasal polyps, and lungs) is described. Additionally, a systematic review of AIP type 1 with testicular and nasal involvement was conducted. Results: The systematic review found two cases of AIP type 1 with testicular involvement and 143 cases with AIP type 1 with nasal cavity involvement. None of them had both testicular and nasal involvement. Conclusions: This is the first case of AIP type 1 with other organ involvement, including testicular and nasal involvement, to be described. The number of patients with nasal and testicular involvement described in the literature is low. Creating awareness of this rare clinical condition is necessary, especially due to the very effective available treatment with corticosteroids and rituximab.
Abstract
Background
The effect of awake prone positioning on intubation rates is not established. The aim of this trial was to investigate if a protocol for awake prone positioning reduces the rate ...of endotracheal intubation compared with standard care among patients with moderate to severe hypoxemic respiratory failure due to COVID-19.
Methods
We conducted a multicenter randomized clinical trial. Adult patients with confirmed COVID-19, high-flow nasal oxygen or noninvasive ventilation for respiratory support and a PaO
2
/FiO
2
ratio ≤ 20 kPa were randomly assigned to a protocol targeting 16 h prone positioning per day or standard care. The primary endpoint was intubation within 30 days. Secondary endpoints included duration of awake prone positioning, 30-day mortality, ventilator-free days, hospital and intensive care unit length of stay, use of noninvasive ventilation, organ support and adverse events. The trial was terminated early due to futility.
Results
Of 141 patients assessed for eligibility, 75 were randomized of whom 39 were allocated to the control group and 36 to the prone group. Within 30 days after enrollment, 13 patients (33%) were intubated in the control group versus 12 patients (33%) in the prone group (HR 1.01 (95% CI 0.46–2.21),
P
= 0.99). Median prone duration was 3.4 h IQR 1.8–8.4 in the control group compared with 9.0 h per day IQR 4.4–10.6 in the prone group (
P
= 0.014). Nine patients (23%) in the control group had pressure sores compared with two patients (6%) in the prone group (difference − 18% (95% CI − 2 to − 33%);
P
= 0.032). There were no other differences in secondary outcomes between groups.
Conclusions
The implemented protocol for awake prone positioning increased duration of prone positioning, but did not reduce the rate of intubation in patients with hypoxemic respiratory failure due to COVID-19 compared to standard care.
Trial registration
ISRCTN54917435. Registered 15 June 2020 (
https://doi.org/10.1186/ISRCTN54917435
).
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