Safety of anti-TNF agents in patients with compensated cirrhosis: a case-control study

Background: There is limited data on the use of anti-TNF agents in patients with concomitant cirrhosis. The aim of this study is to assess the safety of anti-TNF agents in patients with compensated cirrhosis who used these medications for the treatment of an underlying rheumatologic condition or IBD. Methods: Multicenter, retrospective, matched, case-control study. A one to three case-control match was performed. Adults who received anti-TNF therapy were matched to three adults with cirrhosis who did not receive anti-TNF therapy. Patients were matched for etiology of cirrhosis, MELD-Na and age. Primary outcome was the development of hepatic decompensation. Secondary outcomes included development of infectious complications, hepatocellular carcinoma (HCC), extra-hepatic malignancy, and mortality. Results: Eighty patients with cirrhosis who received anti-TNF agents were matched with 240 controls. Median age was 57.2 years. Median MELD-Na for the anti-TNF cohort was seven and median MELD-Na for the controls was eight. The most common etiology of cirrhosis was NAFLD. Anti-TNF therapy did not increase risk of decompensation (HR: 0.91, 95% CI: 0.64–1.30, p = 0.61) nor influence the time to development of a decompensating event. Anti-TNF therapy did not increase the risk of hepatic mortality or need for liver transplantation (HR: 1.18, 95% CI: 0.55–2.53, p = 0.67). Anti-TNF therapy was not associated with an increased risk of serious infection (HR: 1.21, 95% CI: 0.68–2.17, p = 0.52), HCC (OR: 0.45, 95% CI: 0.13–1.57, p = 0.21), or extra-hepatic malignancy (OR: 0.82, 95% CI: 0.29–2.30, p = 0.71). Conclusions: Anti-TNF agents in patients with compensated cirrhosis does not influence the risk of decompensation, serious infections, transplant free survival, or malignancy

On the Role of Correlation and Abstraction in Cross-Modal Multimedia Retrieval

The problem of cross-modal retrieval from multimedia repositories is considered. This problem addresses the design of retrieval systems that support queries across content modalities, e.g. using an image to search for texts. A mathematical formulation is proposed, equating the design of cross-modal retrieval systems to that of isomorphic feature spaces for different content modalities. Two hypotheses are then investigated, regarding the fundamental attributes of these spaces. The first is that low-level cross-modal correlations should be accounted for. The second is that the space should enable semantic abstraction. Three new solutions to the cross-modal retrieval problem are then derived from these hypotheses: correlation matching (CM), an unsupervised method which models cross-modal correlations, semantic matching (SM), a supervised technique that relies on semantic representation, and semantic correlation matching (SCM), which combines both. An extensive evaluation of retrieval performance is conducted to test the validity of the hypotheses. All approaches are shown successful for text retrieval in response to image queries and vice-versa. It is concluded that both hypotheses hold, in a complementary form, although the evidence in favor of the abstraction hypothesis is stronger than that for correlation

Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab

Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy

Magnetic Field Manipulation as a Means of Stabilization

Magnetic levitation technology is rapidly evolving, yet its applications to magnetic stabilization, or using magnetic levitation to stabilize a floating object, have not been fully explored. The goal of our research was to modify current magnetic levitation technology and create a proof-of-concept that paves the way for future research that more specifically explores the real-world applications of magnetic stabilization such as wind turbines. As such, our research was primarily focused on developing a system that could stabilize a levitating magnet using inductors. We accomplished this using data we gathered on several permanent magnets to ensure proper inductor calibration. We then developed code for a microcontroller with a real-time operating system to interface with the system's circuit components. We formulated the microcontroller's code by adapting a general control algorithm to make micro-adjustments to the current provided to our inductors. Our code used the real-time data gathered by a PCB Hall-effect sensor array to make the necessary adjustments to achieve stabilization and levitation. Our findings and methods for code development show encouraging results and suggest that further improvements to the design and calibration of our system should be explored in order to refine our proof-of-concept for specific applications

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The JWST Discovery of the Triply-imaged Type Ia "Supernova H0pe" and Observations of the Galaxy Cluster PLCK G165.7+67.0

A Type Ia supernova (SN) at $z=1.78$ was discovered in James Webb Space Telescope Near Infrared Camera imaging of the galaxy cluster PLCK G165.7+67.0 (G165; $z = 0.35$). The SN is situated 1.5-2kpc from its host galaxy Arc 2 and appears in three different locations as a result of gravitational lensing by G165. These data can yield a value for Hubble's constant using time delays from this multiply-imaged SN Ia that we call "SN H0pe." Over the entire field we identified 21 image multiplicities, confirmed five of them using Near-Infrared Spectrograph (NIRspec), and constructed a new lens model that gives a total mass within 600kpc of ($2.6 \pm 0.3) \times 10^{14}$ M$_{\odot}$. The photometry uncovered a galaxy overdensity at Arc 2's redshift. NIRSpec confirmed six member galaxies, four of which surround Arc 2 with relative velocity $\lesssim$900 km s$^{-1}$ and projected physical extent $\lesssim$33 kpc. Arc 2 dominates the stellar mass ($(5.0 \pm 0.1) \times 10^{11}$ M$_{\odot}$), which is a factor of ten higher than other members of this compact galaxy group. These other group members have specific star formation rates (sSFR) of 2-260Gyr$^{-1}$ derived from the H$\alpha$-line flux corrected for stellar absorption, dust extinction, and slit losses. Another group centered on the dusty star forming galaxy Arc 1 is at $z=2.24$. The total SFR for the Arc 1 group ($gtrsim$ M$_{\odot}$ yr$^{-1}$) translates to a supernova rate of $\sim$1 SNe yr$^{-1}$, suggesting that regular monitoring of this cluster may yield additional SNe.Comment: 27 pages, submitted to Ap

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment

Paper 1: The JWST PEARLS View of the El Gordo Galaxy Cluster and of the Structure It Magnifies

The massive galaxy cluster El Gordo (z=0.87) imprints multitudes of gravitationally lensed arcs onto James Webb Space Telescope (JWST) Near-Infrared Camera (NIRCam) images. Eight bands of NIRCam imaging were obtained in the ``Prime Extragalactic Areas for Reionization and Lensing Science'' (``PEARLS'') program. PSF-matched photometry across Hubble Space Telescope (HST) and NIRCam filters supplies new photometric redshifts. A new light-traces-mass lens model based on 56 image multiplicities identifies the two mass peaks and yields a mass estimate within 500 kpc of ~(7.0 +/- 0.30) x 10^14 Msun. A search for substructure in the 140 cluster members with spectroscopic redshifts confirms the two main mass components. The southeastern mass peak that contains the BCG is more tightly bound than the northwestern one. The virial mass within 1.7 Mpc is (5.1 +/- 0.60) x 10^14 Msun, lower than the lensing mass. A significant transverse velocity component could mean the virial mass is underestimated. We contribute one new member to the previously known z=4.32 galaxy group. Intrinsic (delensed) positions of the five secure group members span a physical extent of ~60 kpc. Thirteen additional candidates selected by spectroscopic/photometric constraints are small and faint with a mean intrinsic luminosity ~2.2 mag fainter than L*. NIRCam imaging admits a fairly wide range of brightnesses and morphologies for the group members, suggesting a more diverse galaxy population in this galaxy overdensity.Comment: 24 pages, accepted by Ap