We discovered that rare tumor cells in primary prostate cancer possess genomic features of castration-resistant prostate cancer. This represents a novel resistance mechanism distinct from the widely ...held notion that prostate cancer becomes resistant to hormonal therapy through a therapy-induced adaptation mechanism.
Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC).
To understand the mechanisms by which subclones within early PCa develop into CRPC.
We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC).
We revealed dynamic transcriptional reprogramming that promotes disease progression among 23226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data.
We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa.
CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa.
Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.
To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non-small cell lung cancer (NSCLC) patients.
This is a single-arm chemotherapy plus phased ipilimumab ...phase II study of 24 treatment-naïve patients with stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles.
Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4
cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8
cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs.
This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies.
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X-ray transmission imaging has been used in a variety of applications for high-resolution measurements based on shape and density. Similarly, X-ray diffraction (XRD) imaging has been used widely for ...molecular structure-based identification of materials. Combining these X-ray methods has the potential to provide high-resolution material identification, exceeding the capabilities of either modality alone. However, XRD imaging methods have been limited in application by their long measurement times and poor spatial resolution, which has generally precluded combined, rapid measurements of X-ray transmission and diffraction. In this work, we present a novel X-ray fan beam coded aperture transmission and diffraction imaging system, developed using commercially available components, for rapid and accurate non-destructive imaging of industrial and biomedical specimens. The imaging system uses a 160 kV Bremsstrahlung X-ray source while achieving a spatial resolution of ≈ 1 × 1 mm
and a spectral accuracy of > 95% with only 15 s exposures per 150 mm fan beam slice. Applications of this technology are reported in geological imaging, pharmaceutical inspection, and medical diagnosis. The performance of the imaging system indicates improved material differentiation relative to transmission imaging alone at scan times suitable for a variety of industrial and biomedical applications.
Esophageal cancer is a deadly cancer with 5-year survival <20%. Although multiple risk factors for esophageal adenocarcinoma (EAC) including obesity, GERD and smoking have been identified, these risk ...factors do not fully explain the rising incidence of EAC. In this study, we evaluated the association between prior history of tonsillectomy and EAC. Our goal was to determine whether tonsillectomies were more frequent in patients with EAC (cases) than in our thoracic surgery controls.
Cases included 452 esophagectomy cases, including 396 with EAC and 56 who underwent esophagectomy for Barrett's esophagus (BE) with high grade dysplasia (HGD). 1,102 thoracic surgery patients with surgical indications other than dysplastic BE or esophageal cancer represented the controls for our analysis. The association of tonsillectomy and HGD/EAC were primarily evaluated by using univariate tests and then verified by logistic regression analysis. Baseline demographics, medical history, and thoracic surgery controls were compared by using χ2 tests or 95% CIs. Significant risk factors were considered as covariates in the multivariate models while evaluating the association between tonsillectomy and HGD/EAC. P-values or odds ratios were estimated with 95% confidence limits to identify significances which was more appropriate.
Tonsillectomy was more common in cases than controls and was found to have a significant association with esophageal cancer (19.9% vs. 12.7%; p-value = 0.0003). This significant association persisted after controlling for other known risk factors/covariates.
A prior history of tonsillectomy was significantly associated with HGD/EAC and may represent an independent risk factor for the development of EAC. However, the underlying biology driving this association remains unclear.
Background/Aims While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized ...countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. Methods A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD ( n = 49) without cirrhosis and controls ( n = 24) matched for gender, age (±5 years), and body mass index (±3 points). Results Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls 365 kcal vs 170 kcal ( p < 0.05). In patients with NAFLD ( n = 6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased ( p = 0.04 and p = 0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. Conclusions The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.
-Assessment of customer satisfaction is a vital component of the laboratory quality improvement program.
-To survey the level of physician satisfaction with hospital clinical laboratory services.
...-Participating institutions provided demographic information and survey results of physician satisfaction, with specific features of clinical laboratory services individually rated on a scale of 5 (excellent) to 1 (poor).
-Eighty-one institutions submitted 2425 surveys. The median overall satisfaction score was 4.2 (10th percentile, 3.6; 90th percentile, 4.6). Of the 16 surveyed areas receiving the highest percentage of excellent/good ratings (combined scores of 4 and 5), quality of results was highest along with test menu adequacy, staff courtesy, and overall satisfaction. Of the 4 categories receiving the lowest percentage values of excellent/good ratings, 3 were related to turnaround time for inpatient "STAT" (tests performed immediately), outpatient STAT, and esoteric tests. The fourth was a new category presented in this survey: ease of electronic order entry. Here, 11.4% (241 of 2121) of physicians assigned below-average (2) or poor (1) scores. The 5 categories deemed most important to physicians included quality of results, turnaround times for inpatient STAT, routine, and outpatient STAT tests, and clinical report format. Overall satisfaction as measured by physician willingness to recommend their laboratory to another physician remains high at 94.5% (2160 of 2286 respondents).
-There is a continued trend of high physician satisfaction and loyalty with clinical laboratory services. Physician dissatisfaction with ease of electronic order entry represents a new challenge. Test turnaround times are persistent areas of dissatisfaction, representing areas for improvement.
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data ...from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.
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•Major pathways of resistance in BRAF-mutant melanoma converge to activate MYC•MYC gene signatures are suppressed on therapy and rebound on progression•MYC activation is necessary and sufficient for resistance to BRAFi in vitro•The MYC-activated, BRAFi-resistant state is associated with targetable vulnerabilities
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, but by combining statistical modeling of tumor data with functional interrogation of resistance models, Singleton et al. show that these pathways converge to activate MYC. BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, informing therapies that select against resistance.
Background
Gastric cancer (GC) accounts for the greatest disparity in cancer mortality between Black and White Americans. Although clinical trials have shown that
Helicobacter pylori
(
Hp
) treatment ...reduces risk of GC
, Hp
testing and treatment is not consistently performed in the US, and may offer an opportunity to improve survival.
Methods
In a diverse retrospective cohort of 99 GC cases diagnosed at Duke University from 2002–2020 (57% Black; 43% white), we examined the association of
Hp
testing and treatment prior to or at cancer diagnosis with overall survival using Cox regression analyses to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs).
Results
Overall, 62% of patients were tested for
Hp
prior to or at GC diagnosis. Of those, 25% tested positive and were treated < 1 year prior to or at diagnosis, 15% tested positive and were treated ≥ 1 year prior to diagnosis, 6% tested positive without evidence of treatment, and 54% tested negative. Compared to never tested,
Hp
testing and treatment < 1 year prior to or at diagnosis was associated with a significantly reduced likelihood of death (HR 0.21, 95% CI 0.08–0.58). The benefit of any
Hp
test and treat prior to or at GC diagnosis was significant even among stage IV patients only (HR, 0.22; 95% CI 0.05–0.96).
Conclusions
These findings support
Hp
testing and treatment for patients at risk of or diagnosed with GC, and suggest
Hp
treatment may provide an opportunity to reduce GC mortality disparities in the US.
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