Yin Yang 1 controls cerebellar astrocyte maturation.

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

Reassessing the chronology of the archaeological site of Anzick.

Found in 1968, the archaeological site of Anzick, Montana, contains the only known Clovis burial. Here, the partial remains of a male infant, Anzick-1, were found in association with a Clovis assemblage of over 100 lithic and osseous artifacts-all red-stained with ochre. The incomplete, unstained cranium of an unassociated, geologically younger individual, Anzick-2, was also recovered. Previous chronometric work has shown an age difference between Anzick-1 and the Clovis assemblage (represented by dates from two antler rod samples). This discrepancy has led to much speculation, with some discounting Anzick-1 as Clovis. To resolve this issue, we present the results of a comprehensive radiocarbon dating program that utilized different pretreatment methods on osseous material from the site. Through this comparative approach, we obtained a robust chronometric dataset that suggests that Anzick-1 is temporally coeval with the dated antler rods. This implies that the individual is indeed temporally associated with the Clovis assemblage.

Stereotactic radiosurgery for the treatment of bulky spine metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) has shown durable local control for the treatment of metastatic diseasespinal metastases. Multilevel disease or epidural or paraspinal involvement present challenges to achieving local control, and this study aims to analyze treatment outcomes for such lesions. METHODS: Patients treated at a single institution with SRS to the spine from 2010-2018 were retrospectively reviewed. Inclusion criteria required clinical follow-up with either a pain assessment or imaging study. Bulky spine metastasis was defined as consisting of multilevel disease or epidural or paraspinal tumor involvement. RESULTS: 54 patients treated for 62 lesions met inclusion criteria. 42 treatments included at least two vertebrae, and 21 and 31 had paraspinal and epidural involvement, respectively. Treatment regimens had a median 24 Gy in 3 fractions to a volume of 37.75 cm3. Median follow-up was 14.36 months, with 5 instances (8%) of local failure. Median overall survival was 13.32 months. Pain improvement was achieved in 47 treatments (76%), and pain improved with treatment (p < 0.0001). Severe pain (HR = 3.08, p = 0.05), additional bone metastases (HR = 4.82, p = 0.05), and paraspinal involvement (HR = 3.93, p < 0.005) were predictive for worse overall survival. Kaplan-Meier analysis demonstrated that prior chemotherapy (p = 0.03) and additional bone metastases (p = 0.02) were predictive of worse overall survival. Grade < 3 toxicity was observed in 19 cases; no grade ≥ 3 side effects were observed. CONCLUSIONS: SRS can effectively treat bulky metastases to the spine, resulting in improvement of pain with minimal toxicity. Severe pain independently predicts for worse overall survival, indicating that treatment prior to worsening of pain is strongly recommended.

The genome of a Late Pleistocene human from a Clovis burial site in western Montana.

Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 (14)C years before present (bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 (14)C years bp (approximately 12,707-12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Mal'ta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.

Long-term sleep disturbance and prescription sleep aid use among cancer survivors in the United States.

PURPOSE: Insomnia and related sleep disorders are common complaints among cancer patients, and use of prescription sleep aids can be high in the treatment setting. The prevalence of sleep disturbance and prescription sleep aid use in the community-dwelling cancer survivorship population, however, remains relatively unexplored. We aim to ascertain the extent to which a cancer diagnosis is associated with sleep disturbances and prescription sleep aid use as measured in several cross sections of individuals across multiple disease sites and time since cancer diagnosis. METHODS: We used data from five cross-sectional cycles of the National Health and Nutrition Evaluation Survey (NHANES) from 2005 to 2014. We identified a total of 2371 individuals who reported a diagnosis of cancer (averaging 61 years old) and 25,788 individuals who did not report a cancer diagnosis (averaging 45 years old). We considered several patient-reported sleep-related outcomes. Multivariate regression analyses, as well as propensity score matching, were used to clarify the relationship between sleep disturbances, prescription sleep aid use, and cancer diagnosis, stratified by time since diagnosis and primary disease site. RESULTS: Reported sleep disturbance was common in cancer survivors, with approximately 34% of patients with a history of cancer reporting having ever been told they had trouble sleeping, compared to 23% of non-cancer patients in the general population with no history of cancer (p < 0.001). Propensity score matching supported a significantly higher rate of trouble sleeping among cancer survivors compared to matched controls. Compared to the general adult population without cancer, cancer survivors 11 or more years past diagnosis were more likely to report being diagnosed with trouble sleeping or a sleep disorder. Further, patients with gynecological cancers were more likely to report prescription sleep aid use, sleep disorders, and trouble sleeping compared to adults without a history of cancer. CONCLUSIONS: Sleeping problems are common in the cancer survivorship population, especially in patients with a long survivorship history and a history of gynecological cancers. Consideration of symptoms of insomnia and sleep disturbance may be helpful in the follow-up care of these patients.

A single-institutional experience with low dose stereotactic body radiation therapy for liver metastases.

AIM: This study reports a single-institutional experience treating liver metastases with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 107 patients with 169 lesions were assessed to determine factors predictive for local control, radiographic response, and overall survival (OS). Machine learning techniques, univariate analysis, and the Kaplan-Meier method were utilized. RESULTS: Patients were treated with a relatively low median dose of 30 Gy in 3 fractions. Fractions were generally delivered once weekly. Median biologically effective dose (BED) was 60 Gy, and the median gross tumor volume (GTV) was 12.16 cc. Median follow-up was 7.36 months. 1-year local control was 75% via the Kaplan-Meier method. On follow-up imaging, 43%, 40%, and 17% of lesions were decreased, stable, and increased in size, respectively. 1-year OS was 46% and varied by primary tumor, with median OS of 34.3, 25.1, 12.5, and 4.6 months for ovarian, breast, colorectal, and lung primary tumors, respectively. Breast and ovarian primary patients had better OS (p < 0.0001), and lung primary patients had worse OS (p = 0.032). Higher BED values, the number of hepatic lesions, and larger GTV were not predictive of local control, radiographic response, or OS. 21% of patients suffered from treatment toxicity, but no grade ≥3 toxicity was reported. CONCLUSION: Relatively low-dose SBRT for liver metastases demonstrated efficacy and minimal toxicity, even for patients with large tumors or multiple lesions. This approach may be useful for patients in whom higher-dose therapy is contraindicated or associated with high risk for toxicity. OS depends largely on the primary tumor.

RelB controls adaptive responses of astrocytes during sterile inflammation.

In response to brain injury or infections, astrocytes become reactive, undergo striking morphological and functional changes, and secrete and respond to a spectrum of inflammatory mediators. We asked whether reactive astrocytes also display adaptive responses during sterile IL-1ß-induced neuroinflammation, which may limit tissue injury associated with many disorders of the central nervous system. We found that astrocytes display days-to-weeks long specific tolerance of cytokine genes, which is coordinated by NF-κB family member, RelB. However, in contrast to innate immune cells, astrocytic tolerance does not involve epigenetic silencing of the cytokine genes. Establishment of tolerance depends on persistent higher levels of RelB in tolerant astrocytes and its phosphorylation on serine 472. Mechanistically, this phosphorylation prevents efficient removal of RelB from cytokine promoters by IκBα and helps to establish tolerance. Importantly, ablation of RelB from astrocytes in mice abolishes tolerance during experimental neuroinflammation in vivo.

Micro Methods for Megafauna: Novel Approaches to Late Quaternary Extinctions and Their Contributions to Faunal Conservation in the Anthropocene.

Drivers of Late Quaternary megafaunal extinctions are relevant to modern conservation policy in a world of growing human population density, climate change, and faunal decline. Traditional debates tend toward global solutions, blaming either dramatic climate change or dispersals of Homo sapiens to new regions. Inherent limitations to archaeological and paleontological data sets often require reliance on scant, poorly resolved lines of evidence. However, recent developments in scientific technologies allow for more local, context-specific approaches. In the present article, we highlight how developments in five such methodologies (radiocarbon approaches, stable isotope analysis, ancient DNA, ancient proteomics, microscopy) have helped drive detailed analysis of specific megafaunal species, their particular ecological settings, and responses to new competitors or predators, climate change, and other external phenomena. The detailed case studies of faunal community composition, extinction chronologies, and demographic trends enabled by these methods examine megafaunal extinctions at scales appropriate for practical understanding of threats against particular species in their habitats today.

Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer.

In breast cancer, 17ß-estradiol (E2) plays critical roles mainly by binding to its canonical receptor, estrogen receptor (ER) α66, and eliciting genomic effects. E2 also triggers rapid, nongenomic responses. E2 activates sphingosine kinase 1 (SphK1), increasing sphingosine-1-phosphate (S1P) that binds to its receptors, leading to important breast cancer signaling. However, the E2 receptor responsible for SphK1 activation has not yet been identified. Here, we demonstrate in triple-negative breast cancer cells, which lack the canonical ERα66 but express the novel splice variant ERα36, that ERα36 is the receptor responsible for E2-induced activation of SphK1 and formation and secretion of S1P and dihydro-S1P, the ligands for S1PRs. Tamoxifen, the first-line endocrine therapy for breast cancer, is an antagonist of ERα66, but an agonist of ERα36, and, like E2, activates SphK1 and markedly increases secretion of S1P. A major problem with tamoxifen therapy is development of acquired resistance. We found that tamoxifen resistance correlated with increased SphK1 and ERα36 expression in tamoxifen-resistant breast cancer cells, in patient-derived xenografts, and in endocrine-resistant breast cancer patients. Our data also indicate that targeting this ERα36 and SphK1 axis may be a therapeutic option to circumvent endocrine resistance and improve patient outcome.

STAT3 suppresses Wnt/ß-catenin signaling during the induction phase of primary Myf5+ brown adipogenesis.

Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1 (UCP1). We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. The inability of STAT3-/- preadipocytes to differentiate can be rescued using Wnt ligand secretion inhibitors when applied during the induction stage. Through chemical inhibition and RNAi, we show that it is the canonical ß-catenin pathway that is responsible for the block in differentiation; inhibition or knockdown of ß-catenin can fully rescue adipogenesis and UCP1 expression in the STAT3-/- adipocytes. During the induction stage, Wnts 1, 3a, and 10b have increased expression in the STAT3-/- adipocytes, potentially explaining the increased levels and activity of ß-catenin. Our results for the first time point towards an interaction between the JAK/STAT pathway and the Wnt/ß-catenin pathway during the early stages of in-vitro adipogenesis.

Late Pleistocene horse and camel hunting at the southern margin of the ice-free corridor: reassessing the age of Wally's Beach, Canada.

The only certain evidence for prehistoric human hunting of horse and camel in North America occurs at the Wally's Beach site, Canada. Here, the butchered remains of seven horses and one camel are associated with 29 nondiagnostic lithic artifacts. Twenty-seven new radiocarbon ages on the bones of these animals revise the age of these kill and butchering localities to 13,300 calibrated y B.P. The tight chronological clustering of the eight kill localities at Wally's Beach indicates these animals were killed over a short period. Human hunting of horse and camel in Canada, coupled with mammoth, mastodon, sloth, and gomphothere hunting documented at other sites from 14,800-12,700 calibrated y B.P., show that 6 of the 36 genera of megafauna that went extinct by approximately 12,700 calibrated y B.P. were hunted by humans. This study shows the importance of accurate geochronology, without which significant discoveries will go unrecognized and the empirical data used to build models explaining the peopling of the Americas and Pleistocene extinctions will be in error.

RelB/p50 complexes regulate cytokine-induced YKL-40 expression.

The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurologic pathologies such as multiple sclerosis and Alzheimer's disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M, synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by oncostatin M and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in nonlymphoid tissues via the canonical activation of the RelB/p50 complexes.

Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-ß amplification loop.

The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNß production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-ß amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.

GAiN: An integrative tool utilizing generative adversarial neural networks for augmented gene expression analysis.

Big genomic data and artificial intelligence (AI) are ushering in an era of precision medicine, providing opportunities to study previously under-represented subtypes and rare diseases rather than categorize them as variances. However, clinical researchers face challenges in accessing such novel technologies as well as reliable methods to study small datasets or subcohorts with unique phenotypes. To address this need, we developed an integrative approach, GAiN, to capture patterns of gene expression from small datasets on the basis of an ensemble of generative adversarial networks (GANs) while leveraging big population data. Where conventional biostatistical methods fail, GAiN reliably discovers differentially expressed genes (DEGs) and enriched pathways between two cohorts with limited numbers of samples (n = 10) when benchmarked against a gold standard. GAiN is freely available at GitHub. Thus, GAiN may serve as a crucial tool for gene expression analysis in scenarios with limited samples, as in the context of rare diseases, under-represented populations, or limited investigator resources.

Unlocking the Power of ChatGPT, Artificial Intelligence, and Large Language Models: Practical Suggestions for Radiation Oncologists.

Recent advances in artificial intelligence (AI), such as generative AI and large language models (LLMs), have generated significant excitement about the potential of AI to revolutionize our lives, work, and interaction with technology. This article explores the practical applications of LLMs, particularly ChatGPT, in the field of radiation oncology. We offer a guide on how radiation oncologists can interact with LLMs like ChatGPT in their routine clinical and administrative tasks, highlighting potential use cases of the present and future. We also highlight limitations and ethical considerations, including the current state of LLMs in decision making, protection of sensitive data, and the important role of human review of AI-generated content.

Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions.

Background: Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions. Methods: Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence curves using death as a competing risk factor were also generated. Results: A total of 147 treated lesions from 83 patients were included: 95 lesions from 51 patients with lung adenocarcinoma and 52 lesions from 32 patients with lung squamous cell carcinoma (SqCC). Median follow-up was 23 [interquartile range (IQR): 9.5-44.5] months for adenocarcinoma, and 11.5 (6-32.25) months for SqCC. Two-year LC was 89% for adenocarcinoma and 77% for SqCC (P=0.04). Median overall survival (OS) was 24.5 (10-46.25) months for adenocarcinoma and 14.5 (7.75-23.25) months for SqCC. Adenocarcinoma had improved LPFS over SqCC (P=0.014). SqCC was associated with increased local failure risk that approached statistical significance (P=0.061) with death as a competing risk. Overall toxicity incidence was 8.2% with no G3+ toxicities. Conclusions: For SBRT-treated oligometastatic or recurrent NSCLC pulmonary lesions, adenocarcinoma histology is associated with improved 2-year LC and LPFS compared to SqCC and reduced incidence of local recurrence (LR) with death as a competing risk.

Late Pleistocene osseous projectile point from the Manis site, Washington-Mastodon hunting in the Pacific Northwest 13,900 years ago.

Bone fragments embedded in a rib of a mastodon (Mammut americanum) from the Manis site, Washington, were digitally excavated and refit to reconstruct an object that is thin and broad, has smooth, shaped faces that converge to sharp lateral edges, and has a plano-convex cross section. These characteristics are consistent with the object being a human-made projectile point. The 13,900-year-old Manis projectile point is morphologically different from later cylindrical osseous points of the 13,000-year-old Clovis complex. The Manis point, which is made of mastodon bone, shows that people predating Clovis made and used osseous weapons to hunt megafauna in the Pacific Northwest during the Bølling-Allerød.

The Association of Radiation Dose With Overall Survival for Patients Treated With Prostate Stereotactic Body Radiation Therapy.

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/ß = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89], P=0.009) on MVA. On Kaplan-Meier analysis, 36.25 Gy was associated with improved survival (p=0.034), with a five-year OS of 92% and 88%, respectively. Conclusions In a multi-institutional retrospective database of 2,214 IR patients treated with prostate SBRT, a prescription dose of 36.25 Gy/5 fx was associated with improved OS vs. 35 Gy/5 fx. Results are hypothesis-generating but do lend support to the current National Comprehensive Cancer Network (NCCN) guidelines that the minimum recommended dose for prostate SBRT is 36.25 Gy/5 fx.

Does Chemo-Radiotherapy Improve Survival Outcomes vs. Radiotherapy Alone for High-Grade cT1 Urothelial Carcinoma of the Bladder?

BACKGROUND: Non-muscle invasive bladder cancer (non-MIBC) that is high-grade and confined to the lamina propria (HGT1) often has an aggressive clinical course. Currently, there is limited data on the comparative effectiveness of RT vs. CRT for HGT1 non-MIBC. We hypothesized that CRT would be associated with improved overall survival (OS) vs. RT in HGT1 bladder cancer. METHODS: Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. Inverse probability of treatment weighting (IPTW) was employed and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. OS was the primary endpoint, and was estimated using the Kaplan-Meier method and log-rank tests. RESULTS: A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio [HR]: 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Four-year OS for the CRT vs. RT alone was 36% and 19%, respectively (log-rank P <.008). CONCLUSION: For patients with HGT1 bladder cancer, concurrent CRT was associated with improved OS compared with radiation alone in a retrospective cohort. These results are hypothesis-generating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies.

Pre-Younger Dryas megafaunal extirpation at Rancho La Brea linked to fire-driven state shift.

The cause, or causes, of the Pleistocene megafaunal extinctions have been difficult to establish, in part because poor spatiotemporal resolution in the fossil record hinders alignment of species disappearances with archeological and environmental data. We obtained 172 new radiocarbon dates on megafauna from Rancho La Brea in California spanning 15.6 to 10.0 thousand calendar years before present (ka). Seven species of extinct megafauna disappeared by 12.9 ka, before the onset of the Younger Dryas. Comparison with high-resolution regional datasets revealed that these disappearances coincided with an ecological state shift that followed aridification and vegetation changes during the Bølling-Allerød (14.69 to 12.89 ka). Time-series modeling implicates large-scale fires as the primary cause of the extirpations, and the catalyst of this state shift may have been mounting human impacts in a drying, warming, and increasingly fire-prone ecosystem.