Milankovitch-paced erosion in the southern Central Andes.

It has long been hypothesized that climate can modify both the pattern and magnitude of erosion in mountainous landscapes, thereby controlling morphology, rates of deformation, and potentially modulating global carbon and nutrient cycles through weathering feedbacks. Although conceptually appealing, geologic evidence for a direct climatic control on erosion has remained ambiguous owing to a lack of high-resolution, long-term terrestrial records and suitable field sites. Here we provide direct terrestrial field evidence for long-term synchrony between erosion rates and Milankovitch-driven, 400-kyr eccentricity cycles using a Plio-Pleistocene cosmogenic radionuclide paleo-erosion rate record from the southern Central Andes. The observed climate-erosion coupling across multiple orbital cycles, when combined with results from the intermediate complexity climate model CLIMBER-2, are consistent with the hypothesis that relatively modest fluctuations in precipitation can cause synchronous and nonlinear responses in erosion rates as landscapes adjust to ever-evolving hydrologic boundary conditions imposed by oscillating climate regimes.

Nitroreductase/Metronidazole-Mediated Ablation and a MATLAB Platform (RpEGEN) for Studying Regeneration of the Zebrafish Retinal Pigment Epithelium.

The retinal pigment epithelium (RPE) resides at the back of the eye and performs functions essential for maintaining the health and integrity of adjacent retinal and vascular tissues. At present, the limited reparative capacity of mammalian RPE, which is restricted to small injuries, has hindered progress to understanding in vivo RPE regenerative processes. Here, a detailed methodology is provided to facilitate the study of in vivo RPE repair utilizing the zebrafish, a vertebrate model capable of robust tissue regeneration. This protocol describes a transgenic nitroreductase/metronidazole (NTR/MTZ)-mediated injury paradigm (rpe65a:nfsB-eGFP), which results in ablation of the central two-thirds of the RPE after 24 h treatment with MTZ, with subsequent tissue recovery. Focus is placed on RPE ablations in larval zebrafish and methods for testing the effects of pharmacological compounds on RPE regeneration are also outlined. Generation and validation of RpEGEN, a MATLAB script created to automate quantification of RPE regeneration based on pigmentation, is also discussed. Beyond active RPE repair mechanisms, this protocol can be expanded to studies of RPE degeneration and injury responses as well as the effects of RPE damage on adjacent retinal and vascular tissues, among other cellular and molecular processes. This zebrafish system holds significant promise in identifying genes, networks, and processes that drive RPE regeneration and RPE disease-related mechanisms, with the long-term goal of applying this knowledge to mammalian systems and, ultimately, toward therapeutic development.

Antiplasmodial activity of the natural product compounds alstonine and himbeline.

Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 µM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC50) 0.17 and 0.58 µM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC50 ~1 µM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets.

Oral and maxillofacial dental care professionals in critical care during the COVID-19 pandemic.

At the peak of the COVID-19 pandemic there was a 'call to arms' across the oral and maxillofacial staff. This article reports on the extended role of the department's dental care professionals (DCPs) and the tremendous opportunity and value that temporary redeployment presented.

Harnessing a decade of data to inform future decisions: Insights into the ongoing hydrocarbon release at Taylor Energy's Mississippi Canyon Block 20 (MC20) site.

The release of oil and gas at Mississippi Canyon Block 20 into the Gulf of Mexico has vexed response officials since 2004 when a regional seafloor failure toppled the Taylor Energy Company platform. Despite the completion of nine intervention wells, releases continue from the seafloor, mostly captured by a recently installed containment system. Toward informing resolution, this work applies chemical forensic and statistical analyses to surface sheens, sediments, and reservoir oil samples. Our results indicate sheens are chemically heterogeneous, contain remnant synthetic hydrocarbons likely discharged from well interventions prior to 2012, and require mixing of multiple chemically-distinct oil groups to explain observed variability in diagnostic ratios. Given the respite and opportunity afforded by containment we suggest leveraging ongoing collection activities to assess release dynamics, as well as engaging the National Academies of Science, Engineering, and Medicine, to evaluate potential solutions, associated risks, and to consider policy ramifications.

Case selection for urological input in planned laparoscopic rectovaginal endometriosis surgery.

BACKGROUND: Surgery for deep endometriosis often requires input from urological surgeons. This study aims to determine pre-operative and intra-operative factors that influence the need for urological input in laparoscopic resection of rectovaginal endometriosis and to assess the usefulness of a scoring system to predict this. METHODS: We conducted a retrospective cohort study of 230 patients undergoing laparoscopic excision of deep endometriosis, at a tertiary referral centre for endometriosis in London UK, 2011 to 2015. Data from pre-operative assessment, surgery and post-operative follow up were analysed and patients were categorised according to their pre-operative and intra-operative risk factors. The primary outcome measure was the requirement of intra-operative input by urological surgeons. RESULTS: The median age was 35 years. In addition to the excision of endometriosis, 19.6% patients (45 patients) underwent hysterectomy, 14.8% (34 patients) required JJ stent placement, 6.1% (14 patients) had bowel resections and 2.6% (6 patients) required an ileostomy. 93.9% (216 patients) were considered normal-risk pre-operatively, of whom 89.4% (193/216) did not require any intra-operative urological input. 10.6% of this normal-risk group (23/216) required JJ stents, of whom 69.6% (16/23) also required a hysterectomy or bowel resection. Post operative complications occurred in 0.9% (2/216) of normal-risk patients, with none having required intra-operative urological reconstruction.Six percent (14 patients) were deemed to be increased-risk pre-operatively, of whom 78.6% (11/14) required JJ stent insertion. Thirty-six percent of increased-risk patients (5/14) had pre-operative renal dysfunction demonstrated on MAG3/DMSA and 80.0% of these (4/5) required intra-operative ureteric reconstruction. CONCLUSIONS: Patients considered normal-risk pre-operatively, planned for excision, without hysterectomy or bowel resection, can be safely managed without specific urology input. Patients with risk-features are highly likely to require urological input, particularly for JJ stent insertion. Patients with pre-operative renal dysfunction, demonstrated on MAG3/DMSA, have a high chance of requiring intra-operative ureteric reconstruction and are best managed with pre-planned reconstructive urologist input.

Force determination in lateral magnetic tweezers combined with TIRF microscopy.

Combining single-molecule techniques with fluorescence microscopy has attracted much interest because it allows the correlation of mechanical measurements with directly visualized DNA : protein interactions. In particular, its combination with total internal reflection fluorescence microscopy (TIRF) is advantageous because of the high signal-to-noise ratio this technique achieves. This, however, requires stretching long DNA molecules across the surface of a flow cell to maximize polymer exposure to the excitation light. In this work, we develop a module to laterally stretch DNA molecules at a constant force, which can be easily implemented in regular or combined magnetic tweezers (MT)-TIRF setups. The pulling module is further characterized in standard flow cells of different thicknesses and glass capillaries, using two types of micrometer size superparamagnetic beads, long DNA molecules, and a home-built device to rotate capillaries with mrad precision. The force range achieved by the magnetic pulling module was between 0.1 and 30 pN. A formalism for estimating forces in flow-stretched tethered beads is also proposed, and the results compared with those of lateral MT, demonstrating that lateral MT achieve higher forces with lower dispersion. Finally, we show the compatibility with TIRF microscopy and the parallelization of measurements by characterizing DNA binding by the centromere-binding protein ParB from Bacillus subtilis. Simultaneous MT pulling and fluorescence imaging demonstrate the non-specific binding of BsParB on DNA under conditions restrictive to condensation.

Severe disruption and disorganization of dermal collagen fibrils in early striae gravidarum.

BACKGROUND: Striae gravidarum (SG), or stretch marks of pregnancy, begin as erythematous streaks and mature into hypopigmented atrophic bands. OBJECTIVES: In order to investigate molecular alterations that may promote atrophy of SG, we investigated dermal type I collagen fibrils, which provide human skin with support. METHODS: We obtained skin samples of recently developed, erythematous abdominal SG from pregnant women. To examine the organization of collagen fibrils, second-harmonic generation imaging was performed using multiphoton microscopy. Immunostaining was used to determine protein expression and localization of type I procollagen, the precursor of type I collagen fibrils. Real-time polymerase chain reaction was used to determine gene expression levels. RESULTS: In control (hip) and stretched normal-appearing perilesional abdominal skin, dermal collagen fibrils were organized as tightly packed, interwoven bundles. In SG, collagen bundles appeared markedly separated, especially in the mid-to-deep dermis. In the spaces separating these bundles, loosely packed wavy collagen fibrils lacking organization as bundles were present. These disorganized fibrils persisted into the postpartum period and failed to form densely packed bundles. Numerous large fibroblasts displaying type I procollagen expression were in close proximity to the disorganized fibrils, suggesting that the fibrils are newly synthesized. Supporting this possibility, immunostaining and gene expression of type I procollagen were increased throughout the dermis of SG. CONCLUSIONS: Early SG display marked separation of collagen bundles and emergence of disorganized collagen fibrils that fail to form bundles. These alterations may reflect ineffective repair of collagen bundles disrupted by intense skin stretching. Persistent disruption of the collagenous extracellular matrix likely promotes formation and atrophy of SG.

Mio-Pliocene aridity in the south-central Andes associated with Southern Hemisphere cold periods.

Although Earth's climate history is best known through marine records, the corresponding continental climatic conditions drive the evolution of terrestrial life. Continental conditions during the latest Miocene are of particular interest because global faunal turnover is roughly synchronous with a period of global glaciation from ∼6.2-5.5 Ma and with the Messinian Salinity Crisis from ∼6.0-5.3 Ma. Despite the climatic and ecological significance of this period, the continental climatic conditions associated with it remain unclear. We address this question using erosion rates of ancient watersheds to constrain Mio-Pliocene climatic conditions in the south-central Andes near 30° S. Our results show two slowdowns in erosion rate, one from ∼6.1-5.2 Ma and another from 3.6 to 3.3 Ma, which we attribute to periods of continental aridity. This view is supported by synchrony with other regional proxies for aridity and with the timing of glacial ?cold" periods as recorded by marine proxies, such as the M2 isotope excursion. We thus conclude that aridity in the south-central Andes is associated with cold periods at high southern latitudes, perhaps due to a northward migration of the Southern Hemisphere westerlies, which disrupted the South American Low Level Jet that delivers moisture to southeastern South America. Colder glacial periods, and possibly associated reductions in atmospheric CO2, thus seem to be an important driver of Mio-Pliocene ecological transitions in the central Andes. Finally, this study demonstrates that paleo-erosion rates can be a powerful proxy for ancient continental climates that lie beyond the reach of most lacustrine and glacial archives.

Molecular basis of retinol anti-ageing properties in naturally aged human skin in vivo.

OBJECTIVE: Retinoic acid has been shown to improve the aged-appearing skin. However, less is known about the anti-ageing effects of retinol (ROL, vitamin A), a precursor of retinoic acid, in aged human skin in vivo. This study aimed to investigate the molecular basis of ROL anti-ageing properties in naturally aged human skin in vivo. METHODS: Sun-protected buttock skin (76 ± 6 years old, n = 12) was topically treated with 0.4% ROL and its vehicle for 7 days. The effects of topical ROL on skin epidermis and dermis were evaluated by immunohistochemistry, in situ hybridization, Northern analysis, real-time RT-PCR and Western analysis. Collagen fibrils nanoscale structure and surface topology were analysed by atomic force microscopy. RESULTS: Topical ROL shows remarkable anti-ageing effects through three major types of skin cells: epidermal keratinocytes, dermal endothelial cells and fibroblasts. Topical ROL significantly increased epidermal thickness by stimulating keratinocytes proliferation and upregulation of c-Jun transcription factor. In addition to epidermal changes, topical ROL significantly improved dermal extracellular matrix (ECM) microenvironment; increasing dermal vascularity by stimulating endothelial cells proliferation and ECM production (type I collagen, fibronectin and elastin) by activating dermal fibroblasts. Topical ROL also stimulates TGF-ß/CTGF pathway, the major regulator of ECM homeostasis, and thus enriched the deposition of ECM in aged human skin in vivo. 0.4% topical ROL achieved similar results as seen with topical retinoic acid, the biologically active form of ROL, without causing noticeable signs of retinoid side effects. CONCLUSION: 0.4% topical ROL shows remarkable anti-ageing effects through improvement of the homeostasis of epidermis and dermis by stimulating the proliferation of keratinocytes and endothelial cells, and activating dermal fibroblasts. These data provide evidence that 0.4% topical ROL is a promising and safe treatment to improve the naturally aged human skin.

Persistence and biodegradation of oil at the ocean floor following Deepwater Horizon.

The 2010 Deepwater Horizon disaster introduced an unprecedented discharge of oil into the deep Gulf of Mexico. Considerable uncertainty has persisted regarding the oil's fate and effects in the deep ocean. In this work we assess the compound-specific rates of biodegradation for 125 aliphatic, aromatic, and biomarker petroleum hydrocarbons that settled to the deep ocean floor following release from the damaged Macondo Well. Based on a dataset comprising measurements of up to 168 distinct hydrocarbon analytes in 2,980 sediment samples collected within 4 y of the spill, we develop a Macondo oil "fingerprint" and conservatively identify a subset of 312 surficial samples consistent with contamination by Macondo oil. Three trends emerge from analysis of the biodegradation rates of 125 individual hydrocarbons in these samples. First, molecular structure served to modulate biodegradation in a predictable fashion, with the simplest structures subject to fastest loss, indicating that biodegradation in the deep ocean progresses similarly to other environments. Second, for many alkanes and polycyclic aromatic hydrocarbons biodegradation occurred in two distinct phases, consistent with rapid loss while oil particles remained suspended followed by slow loss after deposition to the seafloor. Third, the extent of biodegradation for any given sample was influenced by the hydrocarbon content, leading to substantially greater hydrocarbon persistence among the more highly contaminated samples. In addition, under some conditions we find strong evidence for extensive degradation of numerous petroleum biomarkers, notably including the native internal standard 17α(H),21ß(H)-hopane, commonly used to calculate the extent of oil weathering.

Autonomous Marine Robotic Technology Reveals an Expansive Benthic Bacterial Community Relevant to Regional Nitrogen Biogeochemistry.

Benthic accumulations of filamentous, mat-forming bacteria occur throughout the oceans where bisulfide mingles with oxygen or nitrate, providing key but poorly quantified linkages between elemental cycles of carbon, nitrogen and sulfur. Here we used the autonomous underwater vehicle Sentry to conduct a contiguous, 12.5 km photoimaging survey of sea-floor colonies of filamentous bacteria between 80 and 579 m water depth, spanning the continental shelf to the deep suboxic waters of the Santa Barbara Basin (SBB). The survey provided >31 000 images and revealed contiguous, white-colored bacterial colonization coating > ∼80% of the ocean floor and spanning over 1.6 km, between 487 and 523 m water depth. Based on their localization within the stratified waters of the SBB we hypothesize a dynamic and annular biogeochemical zonation by which the bacteria capitalize on periodic flushing events to accumulate and utilize nitrate. Oceanographic time series data bracket the imaging survey and indicate rapid and contemporaneous nitrate loss, while autonomous capture of microbial communities from the benthic boundary layer concurrent with imaging provides possible identities for the responsible bacteria. Based on these observations we explore the ecological context of such mats and their possible importance in the nitrogen cycle of the SBB.

Marked disruption and aberrant regulation of elastic fibres in early striae gravidarum.

BACKGROUND: Striae gravidarum (SG), or 'stretch marks' of pregnancy, begin as erythematous streaks, and mature over months to years to become permanent scar-like bands that may be hypopigmented, atrophic and lax. OBJECTIVES: To investigate early molecular alterations that may promote laxity of mature SG, we investigated the dermal elastic fibre network, which provides human skin with elastic properties. METHODS: We obtained skin samples of newly developed, erythematous abdominal SG in healthy pregnant women. The elastic fibre network was examined by Verhoeff elastic staining and immunofluorescence staining of skin sections. Gene expression was measured by real-time polymerase chain reaction. RESULTS: The normal elastic fibre network appeared markedly disrupted in SG, compared with perilesional abdominal skin or control (normal-appearing hip skin). This disruption was accompanied by the emergence of short, disorganized, thin, thread-like 'fibrils', which were observed prominently in the mid-to-deep dermis. These fibrils were rich in tropoelastin (the main component of normal elastic fibres), and persisted into the postpartum period without forming normal-appearing elastic fibres. The emergence of these fibrils was accompanied by increased gene expression of tropoelastin and fibrillin-1, but not other elastic fibre components, including fibrillin-2 and fibulin-1, -2 or -5. CONCLUSIONS: In early SG, the elastic fibre network appears markedly disrupted, and newly synthesized tropoelastin-rich fibrils emerge, likely as a result of uncoordinated synthesis of elastic fibre components. Because they are thin and disorganized, tropoelastin-rich fibrils likely do not function as normal elastic fibres do. These observations provide the foundations for elucidating pathogenic mechanisms by which laxity may develop in SG.

Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort.

BACKGROUND: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score. METHODS: Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort. RESULTS: In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ(2)=89.0, P<10(-20)) and captured virtually all available prognostic information. CONCLUSIONS: The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.

Simple bone augmentation for alveolar ridge defects.

Dental implant procedures, both surgical placement and preimplant bone augmentation, have become an integral aspect of the oral and maxillofacial surgeon's practice. The number of dental implants placed each year continues to increase as a result of increasing patient exposure and awareness of dental implants, the increased functional and esthetic dental demands of general practitioners and patients, the overall increase in age of the US patient population, and expanded insurance coverage of dental implant-related procedures. This article outlines relevant surgical procedures aimed toward reconstructing alveolar ridge defects to restore intra-arch alveolar discrepancies before restoration-driven dental implant placement.

Fallout plume of submerged oil from Deepwater Horizon.

The sinking of the Deepwater Horizon in the Gulf of Mexico led to uncontrolled emission of oil to the ocean, with an official government estimate of ∼ 5.0 million barrels released. Among the pressing uncertainties surrounding this event is the fate of ∼ 2 million barrels of submerged oil thought to have been trapped in deep-ocean intrusion layers at depths of ∼ 1,000-1,300 m. Here we use chemical distributions of hydrocarbons in >3,000 sediment samples from 534 locations to describe a footprint of oil deposited on the deep-ocean floor. Using a recalcitrant biomarker of crude oil, 17α(H),21ß(H)-hopane (hopane), we have identified a 3,200-km(2) region around the Macondo Well contaminated by ∼ 1.8 ± 1.0 × 10(6) g of excess hopane. Based on spatial, chemical, oceanographic, and mass balance considerations, we calculate that this contamination represents 4-31% of the oil sequestered in the deep ocean. The pattern of contamination points to deep-ocean intrusion layers as the source and is most consistent with dual modes of deposition: a "bathtub ring" formed from an oil-rich layer of water impinging laterally upon the continental slope (at a depth of ∼ 900-1,300 m) and a higher-flux "fallout plume" where suspended oil particles sank to underlying sediment (at a depth of ∼ 1,300-1,700 m). We also suggest that a significant quantity of oil was deposited on the ocean floor outside this area but so far has evaded detection because of its heterogeneous spatial distribution.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib.

BACKGROUND: Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-ß) in patients with advanced GIST following failure of at least imatinib and sunitinib. METHODS: Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. RESULTS: Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR). CONCLUSIONS: Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.