An introduction to the categorical p-adic Langlands program

We give an introduction to the "categorical" approach to the p-adic Langlands program, in both the "Banach" and "analytic" settings.Comment: 210 pages. Preliminary version; comments and corrections would be very welcome, particularly before the end of November when we need to submit this for publicatio

Human Powered Vehicle Frame Design

This report discusses the Human Powered Vehicle Frame Design senior project’s contributions to the design, manufacture, testing, and competition of the Cal Poly Human Powered Vehicle Club’s 2015 vehicle, Sweet Phoenix. The project’s guiding rules and timeline were dictated by the ASME Human Powered Vehicle Challenge (HPVC), held in April 2015. The Club sought to improve upon its previous vehicle, Aria, which suffered from a range of faults including a catastrophic structural failure at the 2014 HPVC. Largely in response to this failure, the Frame Design project’s major focus was Sweet Phoenix’s frame, from concept to manufacturing. During the design process in the Spring and Fall of 2014, several other issues were tackled in order to define the frame’s design parameters. These secondary efforts included the fairing shape, vehicle stability requirements, handling characteristics, and rider ergonomics. A handling prototype was constructed in late Fall 2014, which successfully validated the solutions to these secondary requirements before the final design was constructed. Ultimately, Sweet Phoenix’s frame is a hybrid design – a composite monocoque fairing to which several weldments are mechanically fastened. The team used extensive finite element analysis to evaluate structural properties for both of these frame subsystems during the final development stages. Sweet Phoenix was produced during the Winter quarter of 2015, with much physical help from the HPV Club members and financial support from several sponsors. The production effort was quite successful, in part thanks to two significant manufacturing improvements – sponsored out-of-house machining of the fairing tools, and a frame-to-fairing alignment jig. The vehicle’s construction quality was recognized at HPVC with a “Best Craftsmanship” award. Testing of the final vehicle revealed very low stiffness of the weldments’ fairing mounts, which was resolved by adding additional bracing locations to the fairing. In addition, the team discovered several drivetrain-related issues that were attacked with numerous attempted solutions, but were not solved prior to HPVC. The drivetrain also contributed to localized delamination of the fairing near a chain idler pulley mount. Unfortunately, these drivetrain issues resulted in several broken chains and poor performance in the acceleration-heavy Endurance Event at HPVC. On the other hand, Sweet Phoenix placed 1st in Design and Men’s Sprint, both satisfying results for the Club, and the Frame Design project was an overall success

Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy

AbstractBCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.</jats:p

Metabolic remodeling of white adipose tissue in obesity

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity

An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB₄), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr⁻/⁻ mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB₄ ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy

Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI-chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1). To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIs and chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIs will be published in companion volumes to this paper

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

Abstract Introduction Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively. Conclusions Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy

Morphology, processes and geohazards of giant landslides in and around Agadir Canyon, northwest Africa - Cruise MSM32 - September 25 - October 30, 2013 - Bremen (Germany) - Cádiz (Spain)

Agadir Canyon is one of the largest submarine canyons in the World, supplying giant submarine sediment gravity flows to the Agadir Basin and the wider Moroccan Turbidite System. While the Moroccan Turbidite System is extremely well investigated, almost no data from the source region, i.e. the Agadir Canyon, are available. Understanding why some submarine landslides remain as coherent blocks of sediment throughout their passage downslope, while others mix and disintegrate almost immediately after initial failure, is a major scientific challenge, which was addressed in the Agadir Canyon source region during Cruise MSM32. We collected ~ 1500 km of seismic 2D-lines in combination with a dense net of hydroacoustic data. About 1000 km2 of sea floor were imaged during three deployments of TOBI (deep-towed sidescan sonar operated by the National Oceanography Centre Southampton). A total of 186 m of gravity cores and several giant box cores were recovered at more than 50 stations. CTD casts were collected at nine stations including one 13 hour Yo-yo CTD. The new data show that Agadir canyon is the source area of the world's largest submarine sediment flow, which occurred about 60,000 years ago. Up to 160 km3 of sediment was transported to the deep ocean in a single catastrophic event. For the first time, sediment flows of this scale have been tracked along their entire flow pathway. A major landslide area was identified south of Agadir Canyon. Landslide material enters Agadir canyon in about 2500 m water depth; the material is transported as debrite for at least another 200 km down the canyon. Initial data suggest that the last major slide from this source entered Agadir canyon at least 130,000 years ago. Living deep-water corals were recovered from a large mound field north of Agadir canyon. To our knowledge, these are the first living cold water corals recovered off the coast of Morocco (except for the Gulf of Cadiz). They represent an important link between the known cold-water coral provinces off Mauritania and in the Gulf of Cádiz

Phase II Study of a Non-Platinum–Containing Doublet of Paclitaxel and Pemetrexed with Bevacizumab as Initial Therapy for Patients with Advanced Lung Adenocarcinomas

Many patients with lung cancers cannot receive platinum-containing regimens due to co-morbid medical conditions. We designed the PPB regimen of paclitaxel, pemetrexed, and bevacizumab to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies