One standout feature of human language is our ability to reference external objects and events with socially learned symbols, or words. Exploring the phylogenetic origins of this capacity is ...therefore key to a comprehensive understanding of the evolution of language. While non-human primates can produce vocalizations that refer to external objects in the environment, it is generally accepted that their acoustic structure is fixed and a product of arousal states 1. Indeed, it has been argued that the apparent lack of flexible control over the structure of referential vocalizations represents a key discontinuity with language 2. Here, we demonstrate vocal learning in the acoustic structure of referential food grunts in captive chimpanzees. We found that, following the integration of two groups of adult chimpanzees, the acoustic structure of referential food grunts produced for a specific food converged over 3 years. Acoustic convergence arose independently of preference for the food, and social network analyses indicated this only occurred after strong affiliative relationships were established between the original subgroups. We argue that these data represent the first evidence of non-human animals actively modifying and socially learning the structure of a meaningful referential vocalization from conspecifics. Our findings indicate that primate referential call structure is not simply determined by arousal and that the socially learned nature of referential words in humans likely has ancient evolutionary origins.
•We provide the first evidence for vocal learning of a referential call in non-humans•Immigrant chimpanzees modify referential food call structure to match hosts’ calls•Call convergence only occurred once affiliative social relationships were formed•Call structure was not tied to arousal as calls changed while preferences stayed stable
Watson et al. show socially mediated changes in the structure of chimpanzee food calls. This is the first example of vocal learning in referential vocalizations of any non-human species, and it dispels the myth that the structure of such calls is fixed and tied to arousal. This sheds new light on the evolutionary history of human referential words.
Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. ...Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
Background
Positive surgical margins remain a significant challenge in breast cancer surgery. This report describes the use of a novel, first-in-human ratiometric activatable cell-penetrating peptide ...in breast cancer surgery.
Methods
A two-part, multi-institutional phase 1 trial of AVB-620 with a 3+3 dose escalation and dose-expansion cohorts was conducted. The patients received an infusion of AVB-620 2–20 h before planned lumpectomy/mastectomy and sentinel node biopsy/axillary dissection. Imaging analysis was performed on images obtained from the surgical field as well as post-excision surgical specimens. Pathology reports were obtained to correlate imaging results with histopathologic data. Information on physical adverse events and laboratory abnormalities were recorded.
Results
A total of 27 patients received infusion of AVB-620 and underwent surgical excision of breast cancer. The findings showed no adverse events or laboratory values attributable to infusion of AVB-620. The 8-mg dose was selected from the dose-escalation cohort for use with the expansion cohort based on imaging data. Region-of-interest (ROI) imaging analysis from the 8-mg cohort demonstrated measurable changes between pathology confirmed tumor-positive and tumor-negative tissue.
Conclusion
Intraoperative imaging of surgical specimens after infusion with AVB-620 allowed for real-time tumor detection. Infusion of AVB-620 is safe and may improve intraoperative detection of malignant tissue during breast cancer operations.
The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel DOP) was investigated in the phase II ...I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%–37%), hormone receptor (HR)-positive/HER2-negative (14%–28%), and triple-negative breast cancer (TNBC) (27%–47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.
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•Durvalumab plus olaparib improved chemotherapy efficacy in HER2-negative breast cancer•Immune-rich tumors had greater sensitivity to therapy•Among ER+ cancer, only Mammaprint MP2 cancers benefited from immune checkpoint therapy
Pusztai et al. report findings from the I-SPY2 trial showing durvalumab and olaparib administered with paclitaxel improved pathologic complete response (pCR) rate in HER2-negative breast cancers, including TNBC and ER-positive cancers. Among the ER-positive/HER2-negative cancers, only the highly proliferative, estrogen receptor low, MammaPrint MP2 subset benefited from the combination therapy.
Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment ...decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm.
CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity CDEIS >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689.
Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years SD 1·7; tight control group, 1·0 year 2·3) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 46% of 122 patients) than in the clinical management group (37 30% of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 17% of 122 patients), nasopharyngitis (18 15%), and headache (18 15%) in the tight control group, and worsening Crohn's disease (35 29% of 122 patients), arthralgia (19 16%), and nasopharyngitis (18 15%) in the clinical management group.
CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability.
AbbVie.
Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can ...function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response. Using a GD2-targeting CAR as a model system, we showed that γδT cells of both Vδ1 and Vδ2 subsets could be expanded and transduced to sufficient numbers for clinical studies. The CAR added to the cells’ innate cytotoxicity by enhancing GD2-specific killing of GD2-expressing cancer cell lines. Migration toward tumor cells in vitro was not impaired by the presence of the CAR. Expanded CAR-transduced Vδ2 cells retained the ability to take up tumor antigens and cross presented the processed peptide to responder alpha beta T (αβT) lymphocytes. γδ CAR-T cell products show promise for evaluation in clinical studies of solid tumors.
Chimeric antigen receptors (CARs) have been successfully expressed in human T cells to redirect their cytotoxic effector function against cancer antigens. A rare subset of T cells called gamma delta T cells is shown to be amenable to genetic modification by CARs and to retain the additional functional characteristic of antigen cross presentation.
In the burgeoning field of e-mental health interventions, avatars are increasingly being utilized to facilitate online communication between clients and therapists, and among peers. Avatars are ...digital self-representations, which enable individuals to interact with each other in computer-based virtual environments. In this narrative review, we examine the psychotherapeutic applications of avatars that have been investigated and trialed to date. Five key applications were identified (1) in the formation of online peer support communities; (2) replicating traditional modes of psychotherapy by using avatars as a vehicle to communicate within a wholly virtual environment; (3) using avatar technology to facilitate or augment face-to-face treatment; (4) as part of serious games; and (5) communication with an autonomous virtual therapist. Across these applications, avatars appeared to serve several functions conducive to treatment engagement by (1) facilitating the development of a virtual therapeutic alliance; (2) reducing communication barriers; (3) promoting treatment-seeking through anonymity; (4) promoting expression and exploration of client identity; and (5) enabling therapists to control and manipulate treatment stimuli. Further research into the feasibility and ethical implementation of avatar-based psychotherapies is required.
Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at ...diagnosis with the future development of fibrostenotic CD.
Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes.
In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio HR 3.43, 95% confidence limit CL 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13).
ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.
Breast cancer mortality after ductal carcinoma in situ is rare, making it difficult to predict which patients are at risk and to identify whether risk factors for this outcome are the same as those ...for invasive recurrence. We aimed to identify whether risk factors for invasive recurrences are similar to those for breast cancer death after a diagnosis of pure ductal carcinoma in situ.
The Surveillance, Epidemiology, and End Results Program was queried for female patients diagnosed with pure ductal carcinoma in situ. Cumulative incidence was estimated by treatment group using competing risks. Competing risks regression was then performed for the development of in-breast invasive recurrence with competing risks of breast and non–breast cancer death. Competing risks regression was then again performed for development of breast cancer mortality with the competing risk of non–breast cancer death.
A total of 29,515 patients were identified. Of them, 164 patients suffered breast cancer mortality without an intervening invasive recurrence, and 44 suffered breast cancer mortality after an invasive in-breast recurrence. On competing risks analysis for invasive in-breast recurrence, significant factors included lesion size >5 cm (hazard ratio = 1.59, 95% confidence interval 1.24–2.04, P < .001), diffuse disease (hazard ratio = 0.0005, 95% confidence interval 0.0003–0.0007, P < .001), other race (hazard ratio = 1.29, 95% confidence interval 1.10–1.52, P = .002), Black race (hazard ratio = 1.21, 95% confidence interval 1.01–1.46, P = .04), age at diagnosis (hazard ratio = 0.99, confidence interval 0.98–1.00, P = .02), low-grade disease (hazard ratio = 0.79, 95% confidence interval 0.64–0.96, P = .02), lumpectomy with radiation (hazard ratio = 0.67, 95% confidence interval 0.58-0.77, P < .001), and mastectomy (hazard ratio = 0.36, 95% confidence interval 0.30–0.44, P < .001). Significant factors for breast cancer mortality included age at diagnosis (hazard ratio = 1.04, 95% confidence interval 1.03–1.05, P < .001), Black race (hazard ratio = 2.88, 95% confidence interval 2.08–3.99, P < .001), diffuse disease (hazard ratio = 6.02, 95% confidence interval 1.39–26.07, P = .02), lumpectomy with radiation (hazard ratio = 0.51, 95% confidence interval 0.36–0.72, P < .001), and mastectomy (hazard ratio = 0.60, 95% confidence interval 0.50–0.92, P = .02).
Our results suggested that risk factors for in-breast invasive recurrence after a diagnosis of pure ductal carcinoma in situ differ from risk factors for breast cancer mortality and development of metastatic recurrence. In-breast invasive recurrence is not the only consideration for breast cancer specific mortality in ductal carcinoma in situ patients.
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