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Immunotherapy has only had a modest impact on the treatment of advanced GI malignancies. Microsatellite-stable colorectal cancer and pancreatic adenocarcinoma, the most common GI tumors, have not benefited from treatment with standard immune checkpoint inhibitors. With this huge unmet need, multiple approaches are being tried to overcome barriers to better anticancer outcomes. This article reviews a number of novel approaches to immunotherapy for these tumors. These include the use of novel checkpoint inhibitors such as a modified anti-cytotoxic T lymphocyte-associated antigen-4 antibody and antibodies to lymphocyte-activation gene 3, T cell immunoreceptor with immunoglobulin and ITIM domains, T-cell immunoglobulin-3, CD47, and combinations with signal transduction inhibitors. We will discuss other trials that aim to elicit an antitumor T-cell response using cancer vaccines and oncolytic viruses. Finally, we review attempts to replicate in GI cancers the frequent and durable responses seen in hematologic malignancies with immune cell therapies.

Supplemental material, sj-pdf-1-tam-10.1177_17588359211020547 for Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis by Jun Yin, Shaheenah Dawood, Romain Cohen, Jeff Meyers, John Zalcberg, Takayuki Yoshino, Matthew Seymour, Tim Maughan, Leonard Saltz, Eric Van Cutsem, Alan Venook, Hans-Joachim Schmoll, Richard Goldberg, Paulo Hoff, J. Randolph Hecht, Herbert Hurwitz, Cornelis Punt, Eduard Diaz Rubio, Miriam Koopman, Chiara Cremolini, Volker Heinemann, Christophe Tournigard, Carsten Bokemeyer, Charles Fuchs, Niall Tebbutt, John Souglakos, Jean-Yves Doulliard, Fairooz Kabbinavar, Benoist Chibaudel, Aimery de Gramont, Qian Shi, Axel Grothey and Richard Adams in Therapeutic Advances in Medical Oncology

We aimed to assess the duration of nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA persistence in adults self-confined at home after acute infection; and to identify the associations of SARS-CoV-2 persistence with respiratory virus co-detection and infection transmission. A cross-sectional intra-household study was conducted in metropolitan Barcelona (Spain) during the time period of April to June 2020. Every adult who was the first family member reported as SARS-CoV-2-positive by reverse transcription polymerase chain reaction (RT-PCR) as well as their household child contacts had nasopharyngeal swabs tested by a targeted SARS-CoV-2 RT-PCR and a multiplex viral respiratory panel after a 15 day minimum time lag. Four-hundred and four households (404 adults and 708 children) were enrolled. SARS-CoV-2 RNA was detected in 137 (33.9%) adults and 84 (11.9%) children. Rhinovirus/Enterovirus (RV/EV) was commonly found (83.3%) in co-infection with SARS-CoV-2 in adults. The mean duration of SARS-CoV-2 RNA presence in adults' nasopharynx was 52 days (range 26-83 days). The persistence of SARS-CoV-2 was significantly associated with RV/EV co-infection (adjusted odds ratio (aOR) 9.31; 95% CI 2.57-33.80) and SARS-CoV-2 detection in child contacts (aOR 2.08; 95% CI 1.24-3.51). Prolonged nasopharyngeal SARS-CoV-2 RNA persistence beyond the acute infection phase was frequent in adults quarantined at home during the first epidemic wave; which was associated with RV/EV co-infection and could enhance intra-household infection transmission.

Supplemental material, sj-pdf-1-tam-10.1177_17588359211020547 for Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis by Jun Yin, Shaheenah Dawood, Romain Cohen, Jeff Meyers, John Zalcberg, Takayuki Yoshino, Matthew Seymour, Tim Maughan, Leonard Saltz, Eric Van Cutsem, Alan Venook, Hans-Joachim Schmoll, Richard Goldberg, Paulo Hoff, J. Randolph Hecht, Herbert Hurwitz, Cornelis Punt, Eduard Diaz Rubio, Miriam Koopman, Chiara Cremolini, Volker Heinemann, Christophe Tournigard, Carsten Bokemeyer, Charles Fuchs, Niall Tebbutt, John Souglakos, Jean-Yves Doulliard, Fairooz Kabbinavar, Benoist Chibaudel, Aimery de Gramont, Qian Shi, Axel Grothey and Richard Adams in Therapeutic Advances in Medical Oncology

The Southern Hemisphere summer 2 day wave (TDW) is the most dramatic large-scale event of the upper mesosphere. The winds accelerate over _1 week, may attain > 70 m/s, and are often accompanied by a near disappearance of the diurnal tide and stabilization of the period close to 48 h. We denote this as the phase-locked 2 day wave (PL/TDW). We have examined airglow and meteor radar (MR) wind data from the Andes Lidar Observatory (Cerro Pachon, Chile:30¡S, 289.3¡E), MR data from Darwin (12.5¡S, 131¡E) and airglow and medium frequency radar data from the University of Adelaide (34.7¡S, 138.6¡E) for the behavior of the TDW during the austral summers of 2010, 2012, and 2013. The Cerro Pachon and Adelaide sites are located at similar latitudes separated in longitude by about 120¡. We find a remarkable coincidence between the TDW oscillations at Chile and Adelaide for the period January-February 2010. The oscillations are nearly in phase in terms of local time and the minima and maxima repeat at nearly the same local time from cycle to cycle consistent with a phase-locked wave number 3 TDW. Data for this and other years (including Darwin) show that the amplitude of the diurnal tide decreases when the TDW is largest and that this occurs when the period is close to 48 h. These observations support the proposal that the PL/TDW is a subharmonic parametric instability wherein the diurnal tide transfers energy to a TDW that is resonant at nearly 48 h. ©2015. American Geophysical Union. All Rights Reserved.

The Aerospace Corporation's Nightglow Imager (ANI) observes nighttime OH emission (near 1.6 μm) every 2 s over an approximate 73° field of view. ANI had previously been used to study instability features seen over Maui. Here we describe observations of instabilities seen from 5 to 8 UT on 24 March 2012 over Cerro Pachon, Chile, and compare them with previous results from Maui, with theory, and with Direct Numerical Simulations (DNS). The atmosphere had reduced stability because of the large negative temperature gradients measured by a Na lidar. Thus, regions of dynamical and convective instabilities are expected to form, depending on the value of the Richardson number. Bright primary instabilities are formed with a horizontal wavelength near 9 km and showed the subsequent formation of secondary instabilities, rarely seen over Maui, consistent with the primaries being dynamical instabilities. The ratio of the primary to secondary horizontal wavelength was greater over Chile than over Maui. After dissipation of the instabilities, smaller-scale features appeared with sizes in the buoyancy subrange between 1.5 and 6 km. Their size spectra were consistent with the model of Weinstock (1978) if the turbulence is considered to be increasing. The DNS results produce secondary instabilities with sizes comparable to what is seen in the images although their spectra are somewhat steeper than is observed. However, the DNS results also show that after the complete decay of the primary features, scale sizes considerably smaller than 1 km are produced and these cannot be seen by the ANI instrument.

Small-scale (less than 15 km horizontal wavelength) wavelike structures known as ripples are a common occurrence in OH airglow images. Recent case studies attribute their origin to the presence of either convective or dynamical instabilities. However, little is known about their frequency of occurrence and period. The Maui-MALT Observatory, located at Mt. Haleakala, is instrumented with a Na wind/temperature lidar, which allows the determination of whether the atmosphere is dynamically or convectively unstable, and a fast OH airglow camera which takes images every 3 s with a sensitivity high enough to see the ripples. This study reports on 2 months of observations in October/November 2003 and in August 2004, eight nights of which also included Na lidar measurements. The imager results suggest that instability features occur in the 85- to 90-km region of the atmosphere for around 20% of the time. The nominal observed period for the ripples is between 2 and 4 min. While there are clear night-to-night variations, the average observed period is similar for both the 2003 and 2004 observations. In addition, a few of the small-scale structures are not ripples caused by instabilities but rather have features consistent with their being short horizontal wavelength evanescent waves. Their fractional intensity fluctuations are as large or larger than those of the ripple instabilities. Unlike the instabilities, the origin of the evanescent waves is not determined.

Recently, an association of a specific transforming growth factor alpha (TGFA) haplotype has been reported to occur in patients with nonsyndromic cleft lip and palate (CLP) who had a positive family history of the disorder. We tested linkage of CLP to TGFA in 12 multiplex families with clefting. TGFA haplotypes were constructed on the basis of three polymorphic restriction sites. No haplotype was associated with CLP, and discordant inheritance of TGFA haplotypes was observed in a single informative family. The log odds (LOD) score was -2.1 at theta = .05. These findings indicate that CLP and TGFA are not tightly linked in these families.

Candrea-Hecht J. A. Étymologies roumaines. In: Romania, tome 31 n°122-123, 1902. pp. 296-314.

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by hypoplastic or absent clavicles, large fontanelles, dental anomalies and delayed skeletal development. The phenotype is suggestive of a generalized defect in ossification and is one of the most common skeletal dysplasias not associated with disproportionate stature. To date, no genetic determinants of ossification have been identified. CCD has been mapped to chromosome 6p21, where CBFA1, a gene encoding OSF2/CBFA1, a transcriptional activator of osteoblast differentiation, has been localized. Here, we describe two de novo missense mutations, Met175Arg and Ser191Asn, in the OSF2/CBFA1 gene in two patients with CCD. These two mutations result in substitution of highly conserved amino acids in the DNA-binding domain. DNA-binding studies with the mutant polypeptides show that these amino acid substitutions abolish the DNA-binding ability of OSF2/CBFA1 to its known target sequence. Concurrent studies show that heterozygous nonsense mutations in OSF2/CBFA1 also result in CCD, while mice homozygous for the osf2/cbfa1 mull allele exhibit a more severe lethal phenotype. Thus, these results together suggest that CCD is produced by haploinsufficiency of OSF2/CBFA1 and provide direct genetic evidence that the phenotype is secondary to an alteration of osteoblast differentiation.