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Correlative biomarker analysis: 4A, Shift in balance of tumoral myeloid cells correlates with response. 4B, Baseline circulating AMC and ANC correlate with PFS 4C, High baseline circulating AMC:ALC is associated with disease progression and resistance to immunotherapy 4D, Baseline circulating PMN-MDSC in IOF and ION

Purpose:The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition.Patients and Methods:This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity.Results:The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria.Conclusions:The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Breast implant augmentation is a low-risk procedure with few life-threatening complications. Capsular contracture and rupture/leakage of the implant are the most common complications encountered. Malignant breast implant augmentation-associated lesions are rare, with anaplastic large cell lymphoma being the most common. Squamous cell carcinomas associated with breast implant augmentation are exceedingly rare, with only eight patients reported. Breast implant capsule-associated squamous cell carcinoma occurs in patients with long standing breast implant augmentations (>11 years). We report two additional patients with breast implant capsule-associated squamous cell carcinoma. Review of the literature reveals that invasion beyond the breast implant capsule into the adjacent tissue by the squamous cell carcinoma appears to have negative prognostic implications, and possibly warrants close clinical follow-up.

Background: Extracellular adenosine has been shown to negatively regulate anti-tumor immunity. Adenosine is produced at high levels in the TME as a result of hypoxia-driven tumor cell death. As a result, ATP is released from dying cells generating adenosine via enzymatic dephosphorylation, mainly by ectonucleotidases CD39 & CD73. This results in high extracellular adenosine levels, being elevated 100-500x in the TME. The free adenosine proceeds to binding one of its four known receptors A1, A2a, A2b & A3. The binding of adenosine to A2AR & A2BR contributes to immunosuppression via cyclic AMP pathway. It has been observed that bound A2AR suppress T cell function (CD8+T & NK) while A2BR dampens myeloid cell function and promotes chemotaxis. These concerted actions thereby enhance tumor growth and metastasis. Blocking the binding of adenosine to the A2AR & A2BR results in T-cell activation and infiltration of immune cells in the TME. TT-10 & TT-4 are potent and selective antagonists of A2AR & A2BR. Both agents are being developed for the treatment of advanced cancers individually and as dual inhibitors. Methods: Balb/c mice were implanted with 5 x 104 4T1 cells and randomly assigned to 6 groups per study; (1) Vehicle Control-VC, (2) TT-10, 1 mg/kg, PO, BID (3) TT-4, 3 mg/kg, PO, BID (4) Anti-mPD-1, 200 ug, IP (D4, 8, 14) (5) 1 mg/kg TT-10 + 200 ug Anti-mPD-1 (D4, 8, 14) and (6) TT-4, 3 mg/kg, PO, BID + 200 ug Anti-mPD-1 (D4, 8, 14). Mice were dosed for 21 days, and tumor volume was measured 2x a week. After 21 days post initiation of treatment (31 days post 4T1 cell inoculation), mice were sacrificed, TIL populations were isolated from 4T1 induced tumors and interrogated via Flow. Markers for surface staining included CD45, CD3, CD4, CD8, CD11b, CD49, Ly6G. Results: All implanted mice developed measurable tumors. Mean suppression of tumor growth was observed to be greater in single agent TT-10 (p Conclusions: TT-10 & TT-4 alone was superior (p Citation Format: Desa Rae E. Pastore, Kasim Mookhtiar, Brian Schwartz, Sushant Kumar, Ranganayaki Nagaraj, Ashwinkumar V. Meru. Adenosine receptor antagonists A2AR (TT-10) and A2BR (TT-4) demonstrate anti-tumor activity in 4T1-induced syngeneic breast cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3454.

Plastic is pervasive in modern economies and ecosystems. Freshwater fish ingest microplastics (i.e., particles

The purpose of this study was to assess the preferences of pediatric dentists in Canada and the United States about clinical decision-making related to the placement of direct restorative materials.A cross-sectional web-based survey was used to collect the preference of all active pediatric members of the Royal College of Dentists of Canada and the American Academy of Pediatric Dentistry on the use of direct restorative materials in posterior teeth in healthy, developmentally delayed (DD), and medically compromised (MC) children. Bivariate and multivariate analyses were performed to determine the association between the predictor variables and all materials at two-tailed P0.05.A response rate of 19.3 percent (n equals 762) was achieved. For DD patients, stainless steel crowns were the most preferred material for primary teeth, and a similar frequency of amalgam and composite were preferred for permanent teeth. Amalgam usage was increasingly preferred in the DD population versus healthy and MC patients.Composite resin was the most preferred restoration for Class I, II, and V restorations in primary and permanent teeth in healthy and medically compromised individuals. In DD individuals, stainless steel crowns and amalgam were preferred more frequently.

The purpose of this study was to assess usage, indications, and contraindications for rubber dam isolation (RDI) by pediatric dentists in Canada and the United States.A cross-sectional, web-based, self-administered survey was utilized to collect the opinions of all active pediatric dentist members of the Royal College of Dentists of Canada and the American Academy of Pediatric Dentistry on the use of direct restorative materials in posterior teeth (n equals 4,648; 19.3 percent response rate). The main survey also included a domain on the RDI utilization and its perceived indications and contraindications. Bivariate and multivariate analyses for RDI usage and its predictor were performed at two-tailed P0.05.A response rate of 19.3 percent was obtained. Most participants (72.5 percent) reported using RDI "all the time." The material with the lowest usage of RDI was composite (82 percent) in the primary dentition and stainless steel crown (80.7 percent) in the permanent dentition. The three top-noted reasons for not using RDI included decreased trauma to the patient (66.2 percent), being able to prevent soft tissue from interfering without using RDI (55.9 percent), and decreased time for appointments (45.6 percent).Rubber dam isolation was valued by the majority of pediatric dentists when restoring primary and permanent dentition for all materials.

The purpose of this study was to assess Canadian and American pediatric dentists' preferred level of participation in clinical decision-making.A web-based survey was used to collect the opinions of all active Royal College of Dentists of Canada members and American Academy of Pediatric Dentistry members on the use of direct restorative materials in posterior teeth (n equals 4,648; 19.3 percent response rate). The main survey also included a domain to elicit participants' preferred role in clinical decision-making, ranging from an active role (the dentist takes the primary role in decision-making while considering patients/caregivers opinions) to a passive role (the dentist prefers to have the patient guide the decision-making). Bivariate and multivariate analyses for the preferred role and its predictor were performed (two-tailed P0.05).Fifty-eight percent of participants preferred an active role. The passive role was chosen three times more by those who worked in a hospital-based setting (odds ratio [OR] equals 3.15, 95 percent confidence interval [CI] equals 1.13 to 8.79) or a university-based setting versus a combined setting (OR equals 3.61, 95 percent CI equals 1.11 to 11.77).The majority of participants preferred an active role in decision-making, a role that may not be consistent with a patient-centered practice that emphasizes patient autonomy in decision-making.

The research represents an attempt to evaluate information seeking under conditions relevant to the design of information systems and the training of information analysis. The research effort has as its goal the accomplishment of two major experiments. One which has been completed was designed to assess the effects upon information-seeking and decision-making performance of (a) self- versus controlled-pacing of information input, (b) the rate and variability of rate of information arrival, and (c) the number of decision modifications permitted. A second experiment for which planning and design have been completed at this time will be concerned with the effects upon information-seeking and decision-making performance of (a) the number of decision alternatives, (b) the a priori probabilities of each alternative being correct, and (c) the amount of information available for use in making a decision. (Author)

There has been a growing interest in whether established ecogeographical patterns, such as Bergmann’s rule, explain changes in animal morphology related to climate change. Bergmann’s rule has often been used to predict that body size will decrease as the climate warms, but the predictions about how body size will change are critically dependent on the mechanistic explanation behind the rule. To investigate change in avian body size in western North America, we used two long-term banding data sets from central California, USA; the data spanned 40 years (1971–2010) at one site and 27 years (1983–2009) at the other. We found that wing length of birds captured at both sites has been steadily increasing at a rate of 0.024–0.084% per year. Although changes in body mass were not always significant, when they were, the trend was positive and the magnitudes of significant trends were similar to those for wing length (0.040– 0.112% per year). There was no clear difference between the rates of change of long-distance vs. short-distance migrants or between birds that bred locally compared to those that bred to the north of the sites. Previous studies from other regions of the world have documented decreases in avian body size and have used Bergmann’s rule and increases in mean temperature to explain these shifts. Because our results do not support this pattern, we propose that rather than responding to increasing mean temperatures, avian body size in central California may be influenced by changing climatic variability or changes in primary productivity. More information on regional variation in the rates of avian body size change will be needed to test these hypotheses.

Purpose Teens are at higher risk than other age groups for acquiring sexually transmitted diseases (STDs) because of biological and behavioral risk factors, but they have few STD prevention resources. Little is known about how teens use the Internet to seek this information. A pilot study was conducted to measure audience and information-seeking characteristics of the www.iwannaknow.org Web site. Methods In addition to a formative content analysis and a usability study, an online survey was designed, pilot tested, revised, and launched for three months. This paper briefly describes the first two formative study components, and then focuses on the online survey. Results The content analyses and the usability tests were useful for revising the site content and aesthetics and preparing the online survey. Fewer than half of all participants (N=3,489) were between 13 and 17 (n=1,242), the intended site demographic. Most accessed the Internet from home. The most frequent topic of interest was sexual expression, followed by teen sexuality, virginity, relationships, contraception, and then STD information and these varied by age and gender. Conclusions Methods and findings will assist researchers, Web site developers, and health educators to refine these evaluation methods, develop effective Web sites, and tailor STD prevention messages by age group and gender. The Internet is a cost-effective method for educating teens and those who care for or work with teens about STD risks and prevention, however, more research is needed to assess the behavioral effects of online interventions.

This article discusses from a cross-cultural perspective the process of establishing a new field in a developing country, highlights inherent problems in its sustainability, and demonstrates that field education transcends its traditional boundaries and emerges as a catalyst for organizational change and social development. Illustrations are given of the role of students in initiating organizational changes and of the social development ventures spearheaded by the Field Placement Coordinator and community agencies.

From the 1994 CAIS Conference: The Information Industry in Transition McGill University, Montreal, Quebec. May 25 - 27, 1994.The majority of libraries still provide the majority of their services for free. But fee-based information services attached to non-profit making institutions such as libraries is not a novel concept any longer. The information explosion has brought many changes to, amongst others, the university library and at present industry and commerce rely heavily on the expertise offered by the staff of those libraries.This paper does not propose to address any ideological issues of "feeversus free" but would rather focus on the following: 1 the need for industry and commerce for utilizing the university library and its resources;2 the university library as information broker with reference toinformation skills complemented with specialized subject knowledge and experience 3 the organization of the wide range of services offered and the pricing of these services; and4 a short, but detailed description of INFOBANK, a dynamic andsuccessful regional fee-based information service to industry and commerce at the library of the University of Stellenbosch, South Africa.A university library can therefore be even more effective in promoting access to information by making it available in the community, albeit for a price. Libraries interested in establishing such fee-based services should nevertheless be aware of the pitfalls associated with the creation and management of these services. Knowledge of the latter will undoubtedly help establish a programme that serves the needs of clients whilst contributing towards the overall image of the parent institution.

Ungulates impact woody species' growth and abundance but little is understood about the comparative impacts of different ungulate species on forest expansion in savanna environments. Replacement of native herbivore guilds with livestock [i.e., beef cattle (Bos taurus)] has been hypothesized as a factor facilitating trembling aspen (Populus tremuloides Michx.) encroachment into grasslands of the Northern Great Plains. We used a controlled herbivory study in the Parklands of western Canada to compare the impact of native ungulates and cattle on aspen saplings. Native ungulate treatments included a mixed species guild and sequences of herbivory by different ungulates [bison (Bison bison subsp. bison), elk (Cervus elaphus) then deer (Odocoileus hemionus); or deer, elk, then bison]. Herbivory treatments were replicated in three pastures, within which sets of 40 marked aspen saplings (

A brief overview is provided of the policies, responsibilities, procedures and current projects of the Gift and Exchange Unit of the National Agricultural Library (NAL). Exchange operations which formed a part of the earliest library traditions of the U.S. Department of Agriculture now aid NAL in meeting the challenges of acquisitions operations which must adapt continually during an era of rapid technological change and stringent funding.

La bibliotheque publique peut louer un role important en permettant aux personnes defavorisees d'accroitre la qualite de leur vie quotidienne. Les personnes defavorisees sont celles qui n'ont pas acces aux sources d'information leur permettant de dechiffrer les procedes complexes indispensables pour survivre dans la societe. La contribution analyse la signification exacte de l'expression «information pour survivre», soulignant brievement ses implications sur le financement de la bibliotheque publique. La mise en œuvre, la gestion et l'entretien d'une information de ce type sont decrits ainsi que les conditions de son succes. Le role de la bibliotheque publique dans la reponse a ces defis et aux besoins des communautes defavorisees est explicite

Disruptions in FOXP2, a transcription factor, are the only known monogenic cause of speech and language impairment. We report on clinical findings for two new individuals with a submicroscopic deletion of FOXP2: a boy with severe apraxia of speech and his currently moderately affected mother. A 1.57 Mb deletion on chromosome 7q31 was detected by array comparative genomic hybridization (aCGH). In addition to FOXP2, the patients' deletion involves two other genes, MDFIC and PPP1R3A, neither of which has been associated with speech or language disorders. Thus, findings for these two family members provide informative phenotypic information on FOXP2 haploinsufficiency. Evaluation by a clinical geneticist indicated no major congenital anomalies or dysmorphic features. Evaluations by a clinical psychologist and occupational therapist indicated cognitive-linguistic processing and sensorimotor control deficits, but did not support a diagnosis of autism spectrum disorder. Evaluation by clinical and research speech pathologists confirmed that both patients' speech deficits met contemporary criteria for apraxia of speech. Notably, the patients were not able to laugh, cough, or sneeze spontaneously, replicating findings reported for two other FOXP2 cases and a potential diagnostic sign of nonsyndromic apraxia of speech. Speech severity findings for the boy were not consistent with the hypothesis that loss of maternal FOXP2 should be relatively benign. Better understanding of the behavioral phenotype of FOXP2 disruptions will aid identification of patients, toward an eventual understanding of the pathophysiology of syndromic and nonsyndromic apraxia of speech.