Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer

Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.</p

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Shaping the Glitch: Optimizing Voltage Fault Injection Attacks

Voltage fault injection is a powerful active side channel attack that modifies the execution-flow of a device by creating disturbances on the power supply line. The attack typically aims at skipping security checks or generating side-channels that gradually leak sensitive data, including the firmware code. In this paper we propose a new voltage fault injection technique that generates fully arbitrary voltage glitch waveforms using off-the-shelf and low cost equipment. To show the effectiveness of our setup, we present new, unpublished firmware extraction attacks on six microcontrollers from three major manufacturers: STMicroelectronics, Texas Instruments and Renesas Electronics that, in 2016 declared a market of $1.5 billion,$800 million and $2.5 billion on units sold, respectively. Among the presented attacks, the most challenging ones exploit multiple vulnerabilities and inject over one million glitches, heavily leveraging on the performance and repeatability of the new proposed technique. We perform a thorough evaluation of arbitrary glitch waveforms by comparing the attack performance against two other major V-FI techniques in the literature. Along a responsible disclosure policy, all the vulnerabilities have been timely reported to the manufacturers

Shaping the Glitch: Optimizing Voltage Fault Injection Attacks

Voltage fault injection is a powerful active side channel attack that modifies the execution-flow of a device by creating disturbances on the power supply line. The attack typically aims at skipping security checks or generating side-channels that gradually leak sensitive data, including the firmware code. In this paper we propose a new voltage fault injection technique that generates fully arbitrary voltage glitch waveforms using off-the-shelf and low cost equipment. To show the effectiveness of our setup, we present new, unpublished firmware extraction attacks on six microcontrollers from three major manufacturers: STMicroelectronics, Texas Instruments and Renesas Electronics that, in 2016 declared a market of $1.5 billion,$800 million and $2.5 billion on units sold, respectively. Among the presented attacks, the most challenging ones exploit multiple vulnerabilities and inject over one million glitches, heavily leveraging on the performance and repeatability of the new proposed technique. We perform a thorough evaluation of arbitrary glitch waveforms by comparing the attack performance against two other major V-FI techniques in the literature. Along a responsible disclosure policy, all the vulnerabilities have been timely reported to the manufacturers

A Fast and Cost-effective Design for FPGA-based Fuzzy Rainbow Tradeoffs

Time/memory tradeoffs are general techniques used in cryptanalysis that aim at reducing the computational effort in exchange for a higher memory usage. Among these techniques, one of the most modern algorithms is the fuzzy-rainbow tradeoff, which has notably been used in 2010 to attack the GSM A5/1 cipher. Most of the existing analyses of tradeoff algorithms only take into account the main-memory model, which does not reflect the hierarchical (external) storage model of real world systems. Moreover, to the best of our knowledge, there are no publicly available implementations or designs that show the performance level that can be achieved with modern off-the-shelf hardware. In this paper, we propose a reference hardware and software design for the cryptanalysis of ciphers and one-way functions based on FPGAs, SSDs and the fuzzy rainbow tradeoff algorithm. We evaluate the performance of our design by extending an existing analytical model to account for the actual storage hierarchy, and we estimate an attack time for DES and A5/1 ciphers of less than one second, demonstrating that these ciphers can be cracked in real-time with a budget under 6000e

APDU-Level Attacks in PKCS#11 Devices

In this paper we describe attacks on PKCS#11 devices that we successfully mounted by interacting with the low-level APDU protocol, used to communicate with the device. They exploit proprietary implementation weaknesses which allow attackers to bypass the security enforced at the PKCS#11 level. Some of the attacks leak, as cleartext, sensitive cryptographic keys in devices that were previously considered secure. We present a new threat model for the PKCS#11 middleware and we discuss the new attacks with respect to various attackers and application configurations. All the attacks presented in this paper have been timely reported to manufacturers following a responsible disclosure process

Efficacy of Daptomycin-Containing Regimen for Treatment of Staphylococcal or Enterococcal Vertebral Osteomyelitis: A Prospective Clinical Experience

Vertebral osteomyelitis (VO) is a compelling clinical entity for clinicians, because of its insidious and indolent course that makes diagnosis difficult. A concern is reported about the choice of antibiotic regimens, duration of therapy, and criteria to switch to oral therapy. We conducted a prospective observational study. All consecutive hospitalized patients with a confirmed diagnosis of VO caused by staphylococcal or enterococcal strains were analyzed. The primary endpoint was the analysis of clinical cure at the end of therapy. A propensity score for receiving therapy with daptomycin was added to the model. During the study period, 60 episodes of confirmed VO were observed. The main etiology of infection was methicillin-resistant Staphylococcus aureus (29%). Overall, clinical failure at end of therapy was reported in 11 (18.3%) patients. Logistic regression analysis, after propensity score, showed that &gt;2 vertebrae involved (OR 2.4, CI95% 1.12&ndash;5.24, p = 0.002) and inadequate drainage of infection (OR 4.8, CI95% 2.45&ndash;8.51, p &lt; 0.001) were independently associated with failure of therapy, while the use of a daptomycin-containing-regimen (OR 0.15, CI 95% 0.04&ndash;0.46, p &lt; 0.001) with clinical cure. VO caused by staphylococcal or enterococcal strains is associated with an important rate of clinical failure. Daptomycin-containing regimen was strongly associated with clinical cure. Considering that over 70% of VO etiology is caused by Gram-positive strains but the etiology of infection is obtained in about 75% of cases, these data may help physicians to choose the appropriate antibiotic regimen