Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically ...engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
Intradiscal biologic therapy is a promising strategy for managing intervertebral disc degeneration. However, these therapies require a rich nutrient supply, which may be limited by the transport ...properties of the cartilage endplate (CEP). This study investigated how fluctuations in CEP transport properties impact nutrient diffusion and disc cell survival and function.
Human CEP tissues harvested from six fresh cadaveric lumbar spines (38–66 years old) were placed at the open sides of diffusion chambers. Bovine nucleus pulposus (NP) cells cultured inside the chambers were nourished exclusively by nutrients diffusing through the CEP tissues. After 72 h in culture, depth-dependent NP cell viability and gene expression were measured, and related to CEP transport properties and biochemical composition determined using fluorescence recovery after photobleaching and Fourier transform infrared (FTIR) spectroscopy.
Solute diffusivity varied nearly 4-fold amongst the CEPs studied, and chambers with the least permeable CEPs appeared to have lower aggrecan, collagen-2, and matrix metalloproteinase-2 gene expression, as well as a significantly shorter viable distance from the CEP/nutrient interface. Increasing chamber cell density shortened the viable distance; however, this effect was lost for low-diffusivity CEPs, which suggests that these CEPs may not provide enough nutrient diffusion to satisfy cell demands. Solute diffusivity in the CEP was associated with biochemical composition: low-diffusivity CEPs had greater amounts of collagen and aggrecan, more mineral, and lower cross-link maturity.
CEP transport properties dramatically affect NP cell survival/function. Degeneration-related CEP matrix changes could hinder the success of biologic therapies that require increased nutrient supply.
Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive ...treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24-40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.
Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in ...any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.
The signature of positron annihilation, namely the 511 keV γ-ray line, was first detected coming from the direction of the Galactic center in the 1970s, but the source of Galactic positrons still ...remains a puzzle. The measured flux of the annihilation corresponds to an intense steady source of positron production, with an annihilation rate on the order of ∼1043 . The 511 keV emission is the strongest persistent Galactic γ-ray line signal, and it shows a concentration toward the Galactic center region. An additional low-surface brightness component is aligned with the Galactic disk; however, the morphology of the latter is not well constrained. The Compton Spectrometer and Imager (COSI) is a balloon-borne soft γ-ray (0.2-5 MeV) telescope designed to perform wide-field imaging and high-resolution spectroscopy. One of its major goals is to further our understanding of Galactic positrons. COSI had a 46-day balloon flight in 2016 May-July from Wanaka, New Zealand, and here we report on the detection and spectral and spatial analyses of the 511 keV emission from those observations. To isolate the Galactic positron annihilation emission from instrumental background, we have developed a technique to separate celestial signals using the COMPTEL Data Space. With this method, we find a 7.2 detection of the 511 keV line. We find that the spatial distribution is not consistent with a single point source, and it appears to be broader than what has previously been reported.
Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding ...patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses.
In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes overall survival (OS) and progression-free survival (PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone.
Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS.
Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.
•Treatment of concomitant melanoma with ICI resulted in durable clinical responses despite concomitant CLL.•The ORR to first-line ICI was 41% and median duration of response was 18 months.•Prior treatment for CLL was associated with poor ICI-dependent outcomes, including ORRs, OS, and PFS.•Clinical benefit was achieved without exacerbation of CLL or clearly increased adverse event rates.
Diffusional kurtosis imaging is an extension of DTI but includes non-Gaussian diffusion effects, allowing more comprehensive characterization of microstructural changes during brain development. Our ...purpose was to use diffusional kurtosis imaging to measure age-related microstructural changes in both the WM and GM of the developing human brain.
Diffusional kurtosis imaging was performed in 59 subjects ranging from birth to 4 years 7 months of age. Diffusion metrics, fractional anisotropy, and mean kurtosis were collected from VOIs within multiple WM and GM structures and subsequently analyzed with respect to age. Diffusional kurtosis tractography images at various stages of development were also generated.
Fractional anisotropy and mean kurtosis both showed age-related increases in all WM regions, reflecting progression of diffusional anisotropy throughout development, predominantly in the first 2 years of life (eg, 70% and 157% increase in fractional anisotropy and mean kurtosis, respectively, from birth to 2 years for the splenium). However, mean kurtosis detected continued microstructural changes in WM past the fractional anisotropy plateau, accounting for more delayed isotropic changes (eg, 90% of maximum fractional anisotropy was reached at 5 months, whereas 90% of maximum mean kurtosis occurred at 18 months for the external capsule). Mean kurtosis may also provide greater characterization of GM maturation (eg, the putamen showed no change in fractional anisotropy but an 81% change in mean kurtosis from birth to 4 years 7 months).
Mean kurtosis detects significant microstructural changes consistent with known patterns of brain maturation. In comparison with fractional anisotropy, mean kurtosis may offer a more comprehensive evaluation of age-related microstructural changes in both WM and GM and is potentially a valuable technique for studying brain development.
We report the discovery of two exoplanets transiting high-jitter stars. HAT-P-32b orbits the bright V = 11.289 late-F-early-G dwarf star GSC 3281-00800, with a period P = 2.150008 ? 0.000001 d. The ...stellar and planetary masses and radii depend on the eccentricity of the system, which is poorly constrained due to the high-velocity jitter (~80 m s--1). Assuming a circular orbit, the star has a mass of 1.16 ? 0.04 M and radius of 1.22 ? 0.02 R , while the planet has a mass of 0.860 ? 0.164 M J and a radius of 1.789 ? 0.025 R J. The second planet, HAT-P-33b, orbits the bright V = 11.188 late-F dwarf star GSC 2461-00988, with a period P = 3.474474 ? 0.000001 d. As for HAT-P-32, the stellar and planetary masses and radii of HAT-P-33 depend on the eccentricity, which is poorly constrained due to the high jitter (~50 m s--1). In this case, spectral line bisector spans (BSs) are significantly anti-correlated with the radial velocity residuals, and we are able to use this correlation to reduce the residual rms to ~35 m s--1. We find that the star has a mass of 1.38 ? 0.04 M and a radius of 1.64 ? 0.03 R while the planet has a mass of 0.762 ? 0.101 M J and a radius of 1.686 ? 0.045 R J for an assumed circular orbit. Due to the large BS variations exhibited by both stars we rely on detailed modeling of the photometric light curves to rule out blend scenarios. Both planets are among the largest radii transiting planets discovered to date.
Purpose
There are cognitive changes in primary hyperparathyroidism (PHPT) that improve with parathyroidectomy, but the mechanism of cognitive dysfunction has not been delineated. We assessed if ...cerebrovascular function is impaired in PHPT, improves post-parathyroidectomy and is associated with PTH level and cognitive dysfunction.
Methods
This is an observational study of 43 patients with mild hypercalcemic or normocalcemic PHPT or goiter. At baseline, cerebrovascular function (dynamic cerebral autoregulation and vasomotor reactivity) by transcranial Doppler and neuropsychological function were compared between all three groups. A subset underwent parathyroidectomy or thyroidectomy, and was compared 6 months post-operatively.
Results
Mean cerebrovascular and neuropsychological function was normal and no worse in PHPT compared to controls preoperatively. Higher PTH was associated with worse intracerebral autoregulation (
r
= − 0.43,
p
= 0.02) and worse cognitive performance on some tests. Post-parathyroidectomy, mood improved significantly, but changes did not differ compared to those having thyroidectomy (
p
= 0.84). There was no consistent improvement in cognition or change in vascular function in either surgical group.
Conclusions
Although higher PTH was associated with worse intracerebral autoregulation, cerebrovascular function, cognition and mood were normal in mild PHPT. PTX did not improve vascular or cognitive function. The observed improvement in mood cannot be clearly attributed to PTX. Notwithstanding the small sample size, the results do not support changing current criteria for parathyroidectomy to include cognitive complaints. However, the associations between PTH, cognition and cerebral autoregulation merit future studies in those with more severe hyperparathyroidism.
PDF
