Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

Hair care: Stem cells control immune response during wound repair.

Stem cells heal wounds. In this issue of Immunity, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection.

Prognostic Value of Sequential Organ Failure Assessment (SOFA) Score in Critically-Ill Combat-Injured Patients.

Background: Infection is a frequent and serious complication after combat-related trauma. The Sequential Organ Failure Assessment (SOFA) score has been shown to have predictive value for outcomes, including sepsis and mortality, among various populations. We evaluated the prognostic ability of SOFA score in a combat-related trauma population. Methods: Combat casualties (2009-2014) admitted to Landstuhl Regional Medical Center (LRMC; Germany) intensive care unit (ICU) within 4 days post-injury followed by transition to ICUs in military hospitals in the United States were included. Multivariate logistic regression was used to determine predictive effect of selected variables and receiver operating characteristic (ROC) curve analysis was used to evaluate overall accuracy of SOFA score for infection prediction. Results: Of the 748 patients who met inclusion criteria, 436 (58%) were diagnosed with an infection (32% bloodstream, 63% skin and soft tissue, and 40% pulmonary) and were predominantly young (median 24 years) males. Penetrating trauma accounted for 95% and 86% of injuries among those with and without infections, respectively (p < 0.001). Median LRMC admission SOFA score was 7 (interquartile range [IQR]: 4-9) in patients with infections versus 4 (IQR: 2-6) in patients without infections (p < 0.001). Thirty-day mortality was 2% in both groups. On multivariate regression, LRMC SOFA score was independently associated with infection development (odds ratio: 1.2; 95% confidence interval: 1.1-1.3). The ROC curve analysis revealed an area under the curve of 0.69 for infection prediction, and 0.80 for mortality prediction. Conclusions: The SOFA scores obtained up to 4 days post-injury predict late onset infection occurrence. This study revealed that for every 1 point increase in LRMC SOFA score, the odds of having an infection increases by a factor of 1.2, controlling for other predictors. The use of SOFA score in admission assessments may assist clinicians with identifying those at higher risk of infection following combat-related trauma.

Notes from the Field: Outbreak of Campylobacter jejuni Associated with Consuming Undercooked Chicken Liver Mousse - Clark County, Washington, 2016.

On July 13, 2016, Clark County (Washington) Public Health (CCPH) received a report of diarrheal illness in four of seven members of a single party who dined at a local restaurant on July 6, 2016. The report was received through an online/telephone system for reporting food service-associated illness complaints. Members of the five households in the party reported that their only shared exposure was the restaurant meal. CCPH ordered closure of the restaurant kitchen on July 13, 2016, and began an investigation to identify the source of diarrheal illness and implement additional control measures.

Symbolic arithmetic knowledge without instruction.

Symbolic arithmetic is fundamental to science, technology and economics, but its acquisition by children typically requires years of effort, instruction and drill. When adults perform mental arithmetic, they activate nonsymbolic, approximate number representations, and their performance suffers if this nonsymbolic system is impaired. Nonsymbolic number representations also allow adults, children, and even infants to add or subtract pairs of dot arrays and to compare the resulting sum or difference to a third array, provided that only approximate accuracy is required. Here we report that young children, who have mastered verbal counting and are on the threshold of arithmetic instruction, can build on their nonsymbolic number system to perform symbolic addition and subtraction. Children across a broad socio-economic spectrum solved symbolic problems involving approximate addition or subtraction of large numbers, both in a laboratory test and in a school setting. Aspects of symbolic arithmetic therefore lie within the reach of children who have learned no algorithms for manipulating numerical symbols. Our findings help to delimit the sources of children's difficulties learning symbolic arithmetic, and they suggest ways to enhance children's engagement with formal mathematics.

Kindergarten children's sensitivity to geometry in maps.

Geometrical concepts are critical to a host of human cognitive achievements, from maps to measurement to mathematics, and both the development of these concepts, and their variation by gender, have long been studied. Most studies of geometrical reasoning, however, present children with materials containing both geometric and non-geometric information, and with tasks that are open to multiple solution strategies. Here we present kindergarten children with a task requiring a focus on geometry: navigation in a small-scale space by a purely geometric map. Children spontaneously extracted and used relationships of both distance and angle in the maps, without prior demonstration, instruction, or feedback, but they failed to use the sense information that distinguishes an array from its mirror image. Children of both genders showed a common profile of performance, with boys showing no advantage on this task. These findings provide evidence that some map-reading abilities arise prior to formal instruction, are common to both genders, and are used spontaneously to guide children's spatial behavior.

Dysgonomonas capnocytophagoides Bacteremia in a Patient With Stage IV Colon Adenocarcinoma.

Dysgonomonas capnocytophagoides bacteremia is a rare clinical entity described in only five case reports. Difficulties in the identification and intrinsic multidrug resistance (MDR) of the organism make diagnosis and treatment challenging. We present a case of D. capnocytophagoides bacteremia which highlights the diagnostic and treatment challenges posed by this organism. The case also contributes to the nascent understanding of the clinical profile of patients with D. capnocytophagoides infection and the antimicrobial susceptibility of the organism. A 56-year-old male with advanced colon adenocarcinoma on palliative fluorouracil, leucovorin, and irinotecan (FOLFIRI) presented with abdominal pain. He had been discharged recently following an ICU admission for neutropenic fever with diarrhea and polymicrobial bacteremia resulting in sepsis. Diarrhea resolved during hospitalization. Mediport was retained, surveillance blood cultures remained negative, and he completed 14 days of levofloxacin. Upon readmission for abdominal pain, vital signs were normal and neutropenia had resolved. A Gram-negative rod grew from blood cultures drawn peripherally and from the port with no differential time-to-positivity. Multiple testing platforms were used in an attempt to identify the organism, to include the VERIGENE® Gram-negative blood culture test, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, VITEK ® 2 GN ID, and the Thermo Scientific™ RapID™ NH System (Thermo Scientific, Waltham, MA). Test results from all platforms were either inconclusive or contradictory in their identification of the organism, making the determination of appropriate treatment difficult. Given inconsistent results on multiple testing platforms, the isolate was sent for whole genome sequencing (WGS). Additional workup performed during the hospitalization included a diagnostic paracentesis without evidence of spontaneous bacterial peritonitis, transesophageal echocardiogram without evidence of infective endocarditis, and dental evaluation without evidence of the infectious source. Abdominal CT showed nonspecific terminal ileitis. He was treated for presumed HACEK bacteremia and was transitioned from piperacillin-tazobactam to ceftriaxone to complete a two-week course at hospital discharge. He also received a seven-day course of doxycycline for concomitant, mild lower extremity cellulitis which resolved during hospitalization. Ultimately, antimicrobial susceptibility testing which resulted following discharge was not consistent with the HACEK organism. Testing demonstrated resistance to multiple antimicrobials including ceftriaxone, as well as susceptibility to trimethoprim-sulfamethoxazole (TMP/SMX). WGS ultimately identified the organism as D. capnocytophagoides. Despite ceftriaxone resistance, he reported feeling well at follow-up with negative surveillance blood cultures. This patient shares several features with the few patients previously identified with D. capnocytophagoides bacteremia, including malignancy, recent neutropenia, and presumed gastrointestinal source. As in the small number of prior reported cases, the organism was difficult to identify leading to delay in diagnosis and treatment. The case demonstrates the importance of critical thinking in the face of contradictory test results. Additionally, based on susceptibility profiles described in prior literature, we suspect doxycycline treated his bacteremia.

The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland.

Salivary glands, such as submandibular glands (SMGs), are composed of branched epithelial ductal networks that terminate in acini that together produce, transport and secrete saliva. Here, we show that the transcriptional regulator Yap, a key effector of the Hippo pathway, is required for the proper patterning and morphogenesis of SMG epithelium. Epithelial deletion of Yap in developing SMGs results in the loss of ductal structures, arising from reduced expression of the EGF family member Epiregulin, which we show is required for the expansion of Krt5/Krt14-positive ductal progenitors. We further show that epithelial deletion of the Lats1 and Lats2 genes, which encode kinases that restrict nuclear Yap localization, results in morphogenesis defects accompanied by an expansion of Krt5/Krt14-positive cells. Collectively, our data indicate that Yap-induced Epiregulin signaling promotes the identity of SMG ductal progenitors and that removal of nuclear Yap by Lats1/2-mediated signaling is critical for proper ductal maturation.

Non-symbolic arithmetic abilities and mathematics achievement in the first year of formal schooling.

Children take years to learn symbolic arithmetic. Nevertheless, non-human animals, human adults with no formal education, and human infants represent approximate number in arrays of objects and sequences of events, and they use these capacities to perform approximate addition and subtraction. Do children harness these abilities when they begin to learn school mathematics? In two experiments in different schools, kindergarten children from diverse backgrounds were tested on their non-symbolic arithmetic abilities during the school year, as well as on their mastery of number words and symbols. Performance of non-symbolic arithmetic predicted children's mathematics achievement at the end of the school year, independent of achievement in reading or general intelligence. Non-symbolic arithmetic performance was also related to children's mastery of number words and symbols, which figured prominently in the assessments of mathematics achievement in both schools. Thus, non-symbolic and symbolic numerical abilities are specifically related, in children of diverse socio-economic backgrounds, near the start of mathematics instruction.