Fast transactions for multicore in-memory databases

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 55-57).Though modern multicore machines have sufficient RAM and processors to manage very large in-memory databases, it is not clear what the best strategy for dividing work among cores is. Should each core handle a data partition, avoiding the overhead of concurrency control for most transactions (at the cost of increasing it for cross-partition transactions)? Or should cores access a shared data structure instead? We investigate this question in the context of a fast in-memory database. We describe a new transactionally consistent database storage engine called MAFLINGO. Its cache-centered data structure design provides excellent base key-value store performance, to which we add a new, cache-friendly serializable protocol and support for running large, read-only transactions on a recent snapshot. On a key-value workload, the resulting system introduces negligible performance overhead as compared to a version of our system with transactional support stripped out, while achieving linear scalability versus the number of cores. It also exhibits linear scalability on TPC-C, a popular transactional benchmark. In addition, we show that a partitioning-based approach ceases to be beneficial if the database cannot be partitioned such that only a small fraction of transactions access multiple partitions, making our shared-everything approach more relevant. Finally, based on a survey of results from the literature, we argue that our implementation substantially outperforms previous main-memory databases on TPC-C benchmarks.by Stephen Lyle Tu.S.M

Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells

Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer

HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2-positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P \u3c 0.001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment

Actionable gene-based classification toward precision medicine in gastric cancer

BACKGROUND: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. METHODS: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status. RESULTS: Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster. CONCLUSIONS: This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC

Fucking With Dignity: Public Sex, Queer Intimate Kinship, and How the AIDS Epidemic Bathhouse Closures Constituted a Dignity Taking

In the name of public health, authorities in San Francisco and New York City pursued the closure of gay bathhouses in 1984 and 1985, respectively. We challenge the dominant historical narrative that justified these closings, and through that challenge, we argue that these closures constituted a dignity taking against gay and queer-identified men. Bathhouses were not simply dens of impersonal anonymous sex. They were critical sites of community development and queer kinship. Many governing authorities neither considered the value of these institutions nor grappled with queer understandings of space, contact, intimacy, and belonging. The debates and the closures that followed did substantial cultural and political work to render gay men culpable for their own community’s sudden and relentless demise. As such, these closures were part of a larger anti-gay and anti-HIV cultural discourse that dehumanized and infantilized men who have sex with other men. The bathhouse closings fostered and perpetuated a narrative of culpability, ignited intense divisions within the gay and lesbian communities, and produced within gay men a deep distrust and even fear of governing institutions and of one another. We suggest that this failure to engage with queer logic is ongoing and limits contemporary efforts of dignity restoration that include same-sex marriage recognition. Given the limits of dignity, we conclude by offering some thoughts on what queer dignity restoration might entail

Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine

BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC). METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC. RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy. CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities

Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer

Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as all wild-type , while remaining patients were defined as mutant-type . Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were all wild-type compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and mutant-type RCRC showed significantly worse PFS compared with all wild-type LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC

Impact of Concurrent Genomic Alterations Detected by Comprehensive Genomic Sequencing on Clinical Outcomes in East-Asian Patients with EGFR-Mutated Lung Adenocarcinoma

Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease

Downhole logging as a paeoceanographic tool on ocean drilling program leg 138: Interface between high-resolution stratigraphy and regional syntheses

On Ocean Drilling Program (ODP) Leg 138, standard shipboard procedures were modified to allow for the real-time monitoring of several laboratory core-scanning systems that provide centimeter-scale measurements of saturated bulk density, magnetic susceptibility and digital color reflectance. These continuous, high-resolution data sets were used to ensure the proper offset of multiple holes and to splice together complete sedimentary sections. Typically, the spliced, continuousediment sections were found to be about 10% longer than the section drilled, as measured by the length of the drill string. While the source of this elongation is not yet fully understood, it must be compensated for in order to property determine sediment fluxes and mass accumulation rates. Downhole logging, in conjunction with inverse correlation techniques provided a means to determine where the distortion occurred and to correct back to true in sire depths. Downhole logging also provides a means, through the generation of synthetic seismograms, of precisely relating the paleoceanographic events found in the core record to the high-resolution seismic record. Once correlated to the seismic record, the spatial and temporal extent of paleoceanographic events can be traced well beyond the borehole. Most seismic events in the equatorial Pacific are related to rapid changes in carbonate contenthat, in turn, are related to both productivity events (often expressed as monospecific laminated diatom oozes) and times of enhanced dissolution. While many of these events may have oceanwide extent, others, like the absence of carbonate in the late-Miocene to Recent in the Guatemala Basin have been shown to be regional and confined to only the deeper portions of the Guatemala Basin. As we identify and trace specific paleoceanographic events in the seismic record, we can begin to explore the response of the ocean through gradients of latitude, productivity, and depth

Downhole Logging as a Paeoceanographic Tool on Ocean Drilling Program Leg 138: Interface Between High-Resolution Stratigraphy and Regional Syntheses

On Ocean Drilling Program (ODP) Leg 138, standard shipboard procedures were modified to allow for the real-time monitoring of several laboratory core-scanning systems that provide centimeter-scale measurements of saturated bulk density, magnetic susceptibility and digital color reflectance. These continuous, high-resolution data sets were used to ensure the proper offset of multiple holes and to splice together complete sedimentary sections. Typically, the spliced, continuous sediment sections were found to be about 10% longer than the section drilled, as measured by the length of the drill string. While the source of this elongation is not yet fully understood, it must be compensated for in order to property determine sediment fluxes and mass accumulation rates. Downhole logging, in conjunction with inverse correlation techniques provided a means to determine where the distortion occurred and to correct back to true in situ depths. Downhole logging also provides a means, through the generation of synthetic seismograms, of precisely relating the paleoceanographic events found in the core record to the high-resolution seismic record. Once correlated to the seismic record, the spatial and temporal extent of paleoceanographic events can be traced well beyond the borehole. Most seismic events in the equatorial Pacific are related to rapid changes in carbonate content that, in turn, are related to both productivity events (often expressed as monospecific laminated diatom oozes) and times of enhanced dissolution. While many of these events may have oceanwide extent, others, like the absence of carbonate in the late-Miocene to Recent in the Guatemala Basin have been shown to be regional and confined to only the deeper portions of the Guatemala Basin. As we identify and trace specific paleoceanographic events in the seismic record, we can begin to explore the response of the ocean through gradients of latitude, productivity, and depth