BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...

https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606774/suppl_file/nejmoa1606774_protocol.pdf

Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer

The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61121-X.pdf

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

The Internet has led to the creation of a digital society, where (almost) everything is connected and is accessible from anywhere. However, despite their widespread adoption, traditional IP networks are complex and very hard to manage. It is both difficult to configure the network according to predefined policies, and to reconfigure it to respond to faults, load, and changes. To make matters even more difficult, current networks are also vertically integrated: the control and data planes are bundled together. Software-defined networking (SDN) is an emerging paradigm that promises to change this state of affairs, by breaking vertical integration, separating the network's control logic from the underlying routers and switches, promoting (logical) centralization of network control, and introducing the ability to program the network. The separation of concerns, introduced between the definition of network policies, their implementation in switching hardware, and the forwarding of traffic, is key to the desired flexibility: by breaking the network control problem into tractable pieces, SDN makes it easier to create and introduce new abstractions in networking, simplifying network management and facilitating network evolution. In this paper, we present a comprehensive survey on SDN. We start by introducing the motivation for SDN, explain its main concepts and how it differs from traditional networking, its roots, and the standardization activities regarding this novel paradigm. Next, we present the key building blocks of an SDN infrastructure using a bottom-up, layered approach. We provide an in-depth analysis of the hardware infrastructure, southbound and northbound application programming interfaces (APIs), network virtualization layers, network operating systems (SDN controllers), network programming languages, and network applications. We also look at cross-layer problems such as debugging and troubleshooting. In an effort to anticipate the future evolution of this new paradigm, we discuss the main ongoing research efforts and challenges of SDN. In particular, we address the design of switches and control platforms—with a focus on aspects such as resiliency, scalability, performance, security, and dependability—as well as new opportunities for carrier transport networks and cloud providers. Last but not least, we analyze the position of SDN as a key enabler of a software-defined environment.

https://publications.uni.lu/bitstream/10993/20596/1/survey_on_SDN.pdf

Software-Defined Networking: A Comprehensive Survey

Background and Aims The association between inflammatory bowel disease [IBD] and cancer remains poorly defined in Asian populations. Therefore, we conducted a nationwide population-based study to determine the cancer risk in Korean patients with IBD. Methods Using the National Health Insurance claims data, we collected data on patients diagnosed with IBD (5595 Crohn's disease [CD] and 10 049 ulcerative colitis [UC]) from 2011 to 2014. Standardized incidence ratios [SIRs] of overall and site-specific cancers in IBD patients in comparison with the general population were calculated. Results The overall cancer risk was higher in CD patients [SIR, 2.2; 95% confidence interval, 1.5-3.0 in men and 3.3; 2.4-4.5 in women] and UC patients [1.9; 1.6-2.3 in men and 1.9; 1.5-2.4 in women]. There were significantly increased risks for the following cancers: small bowel cancer [31.2; 3.8-112.8], colorectal cancer [CRC] [3.7; 1.6-7.2] and haematological cancer [4.0; 1.1-10.3] in men with CD; small bowel cancer [61.1; 7.4-220.6], CRC [4.7; 1.5-10.9], liver cancer [15.3; 5.6-33.2], pancreatic cancer [8.6; 1.0-31.0] and haematological cancer [11.0; 3.6-25.7] in women with CD; CRC [2.1; 1.3-3.3] and cancer of the prostate [3.5; 2.1-5.5], brain/central nervous system [6.1; 1.3-17.9] and thyroid [2.2; 1.1-3.9] in men with UC; and CRC [3.0; 1.5-5.3], cancer of the liver [4.4; 1.6-9.7] and cervix uteri [5.7; 2.4-11.1], and haematological cancer [3.5; 1.1-8.1] in women with UC. Women with CD had an increased risk of non-Hodgkin lymphoma [NHL] and leukaemia. Women with UC had an increased risk of NHL. Conclusions Korean patients with IBD are at increased risk for overall, intestinal and haematological cancer.

Cancer Risk in the Early Stages of Inflammatory Bowel Disease in Korean Patients: A Nationwide Population-based Study.

Owing to the trend of faster and denser circuit design, the dielectric properties of packaging materials for semi-conductors will have greater influence on performance and reliability. Also, as chips become more densely packaged, thermal dissipation becomes a critical reliability issue. Consequently, four important properties for manufacturing semi-conductor packaging are: low values of dielectric constants, high values of thermal conductivity, relatively low values of thermal expansion coefficients, and low cost. Thus, in this study, AlN (Aluminum Nitride) was selected as the filler for an epoxy matrix to achieve increased performance of an EMC. As a result, the thermal conductivity of an EMC filled with 70 vol% of A1N increased as much as 7-8 times compared with the EMC filled with a crystalline silica (vol. 70 %). When more than 60 vol% of A1N was added to the EMC, the dielectric constants and thermal expansion coefficient decreased rapidly.

Thermally conductive EMC (epoxy molding compound) for microelectronic encapsulation

Background The aim of this study was to investigate the antiinflammatory effects of Bifidobacterium lactis on intestinal epithelial cells (IECs) and on experimental acute murine colitis and its tumor prevention effects on colitis-associated cancer (CAC) in mice. Methods Human HT-29 cells were stimulated with IL-1beta, lipopolysaccharides, or tumor necrosis factor-alpha with and without B. lactis, and the effects of B. lactis on nuclear factor kappa B (NF-kappaB) signaling in IEC were examined. For in vivo study, dextran sulfate sodium (DSS)-treated mice were fed with and without B. lactis. Finally, we induced colonic tumors in mice by azoxymethane (AOM) and DSS and evaluated the effects of B. lactis on tumor growth. Results B. lactis significantly suppressed NF-kappaB activation, including NF-kappaB-binding activity and NF-kappaB-dependent reporter gene expression in a dose-dependent manner, and suppressed IkappaB-alpha degradation, which correlated with the downregulation of NF-kappaB-dependent gene products. Moreover, B. lactis suppressed the development of acute colitis in mice. Compared with the DSS group, the severity of DSS-induced colitis as assessed by disease activity index, colon length, and histological score was reduced in the B. lactis-treated group. In the CAC model, the mean number and size of tumors in the B. lactis-treated group were significantly lower than those in the AOM group. Conclusions Our data demonstrate that B. lactis inhibits NF-kappaB and NF-kappaB-regulated genes in IEC and prevents acute colitis and CAC in mice. These results suggest that B. lactis could be a potential preventive agent for CAC as well as a therapeutic agent for inflammatory bowel disease.

Bifidobacterium lactis inhibits NF-κB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice

The purpose of this study was to extend the application of self-expandable metallic stents by investigating their usefulness in treating colorectal obstructions caused by unresectable extrinsic tumors. From January 2000 to November 2005, a total of 60 colorectal stenting procedures were performed, and 57 stents were deployed in 39 patients with extrinsic tumors. The success rate and complications were analyzed retrospectively. The most common etiology and location of obstruction were advanced gastric cancer and transverse colon. Technical success was 34 of 39 patients (87.2 percent). The causes of technical failure were immediate stent migration (n = 1), technical problems (n = 1), and access failure because of bowel immobilization (n = 3). Clinical success was 32 of 34 technical successes (82.1 percent). The two patients without clinical success had multifocal strictures of the bowel. Complications occurred in 22 of 57 stents (38.6 percent), including stent reobstruction (n = 14) and stent migration (n = 5). All of stent migrations except one developed with covered stents. In patients with colonic obstruction caused by extrinsic tumors, stent insertion provided effective symptom relief and can be a reasonable alternative choice to a colostomy. An uncovered stent might be more preferable, considering less migration and remaining short life expectancy, compared with a covered stent.

Clinical Application of Self-Expandable Metallic Stent for Treatment of Colorectal Obstruction Caused by Extrinsic Invasive Tumors

Inflammatory bowel disease (IBD) describes chronic inflammatory disease of the intestines and has a variable course; Crohn's disease and ulcerative colitis comprise the two main forms of the condition. Although IBD occurs worldwide, its epidemiologic and clinical characteristics vary depending upon the geographic location and the ethnicity of the population. Identifying the characteristic features of IBD in populations living in different geographical locations and with different ethnicities may provide significant clues about its etiology and pathophysiology, which in turn may be helpful in the development of more appropriate treatment strategies for IBD for these different populations. Therefore, it is important for each country and region to evaluate critically the epidemiology, genomics, and clinical characteristics of IBD among its own population. We have performed a critical review of the recent data in Korea, and describe herein the current epidemiologic and genotypic status, as well as the clinical manifestations and therapeutic responses of IBD that are unique to Korean patients.

/pdf/inflammatory-bowel-disease-in-korea-epidemiological-genomic-2j5ku5acqx.pdf

Won Ho Kim

Papers

Cancer Risk in the Early Stages of Inflammatory Bowel Disease in Korean Patients: A Nationwide Population-based Study.

Thermally conductive EMC (epoxy molding compound) for microelectronic encapsulation

Bifidobacterium lactis inhibits NF-κB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice

Clinical Application of Self-Expandable Metallic Stent for Treatment of Colorectal Obstruction Caused by Extrinsic Invasive Tumors

Inflammatory Bowel Disease in Korea: Epidemiological, Genomic, Clinical, and Therapeutic Characteristics