BACKGROUND:
Pediatric glioblastomas (pGBM) are characterized by overlapping and unique molecular driver mutations compared to their adult counterparts. Primary cell cultures and patient-derived ...xenograft (PDX) models of pGBM are rare which may contribute to difficulty in advancing patient outcomes. We have established an orthotopic PDX mouse model from a pGBM resected from a 12 yo male with recurrent disease. The patient received focal radiation and several chemotherapy regimens prior to the recurrence leading to this tumor resection.
METHODS:
The surgical tumor specimen was dissociated and directly implanted into the brains of immunocompromised (NSG) mice. DNA and immunohistochemical analyses of the patient tumor and PDX were performed. Multiple in vitro culture conditions were tested on the dissociated primary tumor cells and PDX tumor cells.
RESULTS:
Implantation of the patient tumor cells in mice resulted in tumor growth after 120–250 days. Tumors were serially transplanted successfully. Attempts to establish in vitro cell cultures from primary tumor and from established PDX tumors failed. DNA sequencing of the patient tumor sample and tumors from each PDX generation revealed the H3F3A G34R mutation characteristic of cortical pGBM, and mutations in the TP53, PTEN and PIK3CA genes, all of which were conserved in PDX tumors. Interestingly, the patient tumor showed evidence of telomerase activity and alternative lengthening of telomeres (ALT) as did the PDX tumors. The combined PTEN and PIK3CA mutations in this tumor resulted in activation of the PI3K-mTOR pathway. Treatment of tumor-bearing mice with an mTOR or PI3K inhibitor resulted in suppression of the pathway and reduced proliferation.
CONCLUSION:
This pGBM PDX model conserved key driver mutations and pathways from the patient tumor. In vitro culture of pGBM can be extremely challenging to establish and more difficult methods such as orthotopic PDX may be required to study these tumors.
Early detection of emerging SARS-CoV-2 variants is critical to guiding rapid risk assessments, providing clear and timely communication messages, and coordinating public health action. CDC identifies ...and monitors novel SARS-CoV-2 variants through diverse surveillance approaches, including genomic, wastewater, traveler-based, and digital public health surveillance (e.g., global data repositories, news, and social media). The SARS-CoV-2 variant BA.2.86 was first sequenced in Israel and reported on August 13, 2023. The first U.S. COVID-19 case caused by this variant was reported on August 17, 2023, after a patient received testing for SARS-CoV-2 at a health care facility on August 3. In the following month, eight additional U.S. states detected BA.2.86 across various surveillance systems, including specimens from health care settings, wastewater surveillance, and traveler-based genomic surveillance. As of October 23, 2023, sequences have been reported from at least 32 countries. Continued variant tracking and further evidence are needed to evaluate the full public health impact of BA.2.86. Timely genomic sequence submissions to global public databases aided early detection of BA.2.86 despite the decline in the number of specimens being sequenced during the past year. This report describes how multicomponent surveillance and genomic sequencing were used in real time to track the emergence and transmission of the BA.2.86 variant. This surveillance approach provides valuable information regarding implementing and sustaining comprehensive surveillance not only for novel SARS-CoV-2 variants but also for future pathogen threats.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
This study tested whether opiate dependence, tobacco smoking, or their combination accompanied impaired performance on the gambling task (GT), which tests decision-making. GT previously detected ...impairments in patients with lesions of the ventromedial prefrontal cortex and in substance abusers. Four groups were matched on demographic characteristics and intelligence: methadone-maintained smokers (
n=9) and nonsmokers (
n=9), and control (i.e., not opiate-dependent) smokers (
n=9) and nonsmokers (
n=10). The Wisconsin Card Sorting Task (WCST) was administered to test whether differences in GT performance reflected generalized deficits in prefrontal cortical function. While there were no significant group differences on the WCST, groups differed significantly on GT performance (
F(3,31)=2.95,
P=0.048), controlling for depressive symptom ratings and childhood attention deficit hyperactivity disorder. Methadone-maintained smokers (but not nonsmokers) performed more poorly than either of the two control groups (
P=0.007 versus smokers;
P=0.024 versus nonsmokers). In a planned analysis of methadone-maintained subjects, smokers scored more poorly on GT than nonsmokers (
F(1,18)=5.64,
P=0.032) and had more treatment failures (67% heroin use during the last 30 days versus 20%). The findings suggest that among opiate-dependent individuals, tobacco smoking may be a marker for a more severe form of substance abuse disorder, reflecting impaired decision-making, as modeled by GT.
Calorie restriction (CR) and late-onset CR enhance longevity in many organisms. Resource allocation theory suggests that longevity is enhanced by increasing somatic storage, at the expense of current ...reproduction. Phytophagous insects accumulate amino acids as hemolymph storage proteins for major developmental events. We hypothesized that protein storage is involved in life extension from CR. In a longitudinal experiment, we tested whether CR altered protein storage in female grasshoppers. Individuals on CR (60 or 70% of
ad libitum) or late-onset CR had at least 60% greater longevity than
ad libitum individuals. Age at first oviposition, dry mass of the first clutch, or lifetime fecundity were not affected by CR, but CR did increase the number of clutches produced. Most important, females on life-extending CR and late-onset CR did not differ in the concentration of hemolymph storage of proteins in comparison to
ad libitum females. Protein storage changed with time in all groups, demonstrating sufficient sensitivity in our methods. Previous experiments have shown that severe CR (∼30% of
ad libitum) can reduce hemolymph storage. Therefore, the reduction in intake needed to extend lifespan is not sufficient to reduce protein storage in the hemolymph. These results do not support the hypothesis that protein storage is involved in life extension from CR.
The Multi-sensor Airborne Radiation Survey (MARS) instrument Fast, J.E.; Aalseth, C.E.; Asner, D.M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2013, Letnik:
698
Journal Article
Recenzirano
The Multi-sensor Airborne Radiation Survey (MARS) project has developed a new single cryostat detector array design for high purity germanium (HPGe) gama ray spectrometers that achieves the high ...detection efficiency required for stand-off detection and actionable characterization of radiological threats. This approach is necessary since a high efficiency HPGe detector can only be built as an array due to limitations in growing large germanium crystals. The system is ruggedized and shock mounted for use in a variety of field applications, including airborne and maritime operations.
The Pacific Northwest National Laboratory (PNNL) is currently developing a custom software suite capable of automating many of the tasks required to accurately analyze coincident signals within gamma ...spectrometer arrays. During the course of this work, significant crosstalk was identified in the energy determination for spectra collected with a new low-background intrinsic germanium (HPGe) array at PNNL. The HPGe array is designed for high detection efficiency, ultra-low-background performance, and sensitive γ–γ coincidence detection. The first half of the array, a single cryostat containing seven HPGe crystals, was recently installed into a new shallow underground laboratory facility. This update will present a brief review of the germanium array, describe the observed crosstalk, and present a straight-forward empirical correction that significantly reduces the impact of this crosstalk on the spectroscopic performance of the system.
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