Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

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Methods for repeated recording in visual cortex of anesthetized and awake behaving infant monkeys.

This report describes methods for making repeated recordings from visual cortex in infant macaque monkeys (age range 5 weeks to 7 months) both under nitrous oxide anesthesia and in an alert behaving state. These methods permitted successful collection of single-unit data from inferior temporal cortex and other areas in a longitudinal fashion from individual infants. For the anesthetized experiments, modifications of our standard techniques for surgical preparation and maintenance of the animal in an anesthetized, artificially ventilated state permitted repeated recording sessions while assuring the animal's continued health and normal growth. Following implantation with an eye coil, monkeys as young as 5 weeks could be trained to perform a fixation task during alert recording sessions which were likewise performed on a repeated basis with maintained health and development. Further, comparison of results from anesthetized and awake recording sessions indicates that alert recording is preferable for collecting certain types of data from visual cortex in infant monkeys.     

Tumor necrosis factor-related apoptosis-inducing ligand can induce apoptosis in subsets of premalignant cells

During the transformation from a normal to a malignant cell, several mutations are required to bypass the pathways responsible for controlling proliferation. Premalignant cells have acquired some, but not all of these mutations and consequently have not yet attained a malignant phenotype characterized by tumor formation in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in malignant cells while sparing normal ones and is currently being considered as adjuvant therapy for various human malignancies. Whether TRAIL is effective in inducing apoptosis in premalignant cells is unclear, however. We studied the effect of TRAIL on two human premalignant cell lines the SV7tert and HA1E cells. Both cell lines had been immortalized by the addition of simian virus 40 large T antigen and the telomerase subunit hTERT, but had not been transformed into malignant cells. TRAIL initiated apoptosis by activating both the mitochondrial-independent and -dependent apoptotic pathways in both cell lines at relatively low doses whereas it had no effect on normal human pulmonary artery smooth muscle cells even at high doses. These results suggest that TRAIL can induce apoptosis in premalignant cells and suggests a novel therapy for the treatment of premalignant lesions in vivo.     

Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4+ T Cell Responsiveness

Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects’ blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4⁺ T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4⁺ T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4⁺ T cell immune responsiveness.     

A Nationwide Survey of Financing Health-Related Services for Special Education Students

The Individuals with Disability Education Act (IDEA) requires state educational systems to provide school-based, health related services (RS). This survey determined the financing arrangements used by states for health-related services for school-aged children with disabilities. A survey was sent to directors of special education, Medicaid, and public health departments in each of the 50 states. Financial patterns for RS were sought at the state level for children ages 3-21 with disabilities for the 1993-1994 school year, the most recent year for which complete financial data were available. Univariate analyses probed the relationship between systems' variables and the extent of Medicaid usage by local education agencies. Respondents reported that schools tapped traditional health resources to supplement educational dollars in paying for related services in schools. Medicaid was by far the most common source with 29 states reporting established mechanisms for recouping Medicaid dollars and 10 states reporting phase-in activities. Seventeen states reported that departments of public health played some role in administration, training, and demonstrations, but only six states provided specific dollars for related services through the department. Use of private insurance was reported sporadically with only one state indicating a specific state-level program. Correlates of increased Medicaid usage were presence of interagency agreements (IAAs) (OR 11.1, p = 0.002), having specific personnel for school-based medical assistance (OR 17.7, p = 0.001), and utilizing school nursing services as a Medicaid optional service (OR 4.2, p = 0.048).     

Applying cognitive-behavioral psychotherapy to the chronically ill elderly: treatment issues and case illustration.

A large percentage of older adults must endure at least one chronic medical illness. Clinically significant depression and anxiety are common among these patients. Specific psychotherapy approaches as well as adaptations required to address the unique issues of this population have not been delineated in the literature. We outline a cognitive-behavioral therapy approach and discuss five treatment issues we have found to be important for this population. These issues include: (1) resolving practical barriers to participation; (2) accepting depression as a separate and reversible problem; (3) limiting excess disability; (4) counteracting the loss of important social roles and autonomy; and (5) challenging the perception of being a "burden." A case study of a chronic obstructive pulmonary disease (COPD) patient with depression is presented and recommendations for future research are suggested.     

Stimulus selectivity and state dependence of activity in inferior temporal cortex of infant monkeys.

Inferior temporal cortex is necessary for visual object recognition in adult primates but is less critical in infants. Nonetheless, in macaques as young as 6 weeks old, inferior temporal neurons showed adult-like visual response properties, including form selectivity and bilateral receptive fields, indicating that extended maturation and visual experience may not be necessary for adult-like encoding of complex objects. However, before the animals were 4 months old, visual responsiveness was found in inferior temporal cortex only in awake monkeys performing a behavioral task and not in anesthetized ones, suggesting that extraretinal factors profoundly influence function in "association" cortex in developing as well as mature animals.     

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997     

Guidelines for the diagnosis and management of blunt aortic injury: an EAST Practice Management Guidelines Work Group

In summary, BAI is a lethal result of severe blunt trauma. It should be considered in all patients who sustained injury by a deceleration or acceleration mechanism, especially in the face of physical or radiographic findings suggestive of mediastinal injury. Angiography remains the "gold standard" for diagnosis, although CT scanning is taking more of a role, especially for screening. Diagnosis should be followed by prompt surgical repair using some method of distal perfusion to minimize renal and spinal cord ischemia. If prompt repair is not feasible because of other injuries or comorbidities, medical control of blood pressure is warranted in the interim.     

Human fluids alter DNA-acquisition in Acinetobacter baumannii

Transformation is one of the mechanisms of acquisition of foreign genetic material leading to the emergence of multidrug resistant (MDR) bacteria. Recently, human serum albumin (HSA) was shown to specifically increase transformation frequency in the nosocomial pathogen Acinetobacter baumannii. To further assess the relevance of HSA as a possible modulator of A. baumannii transformation in host-pathogen interactions, in this work we examined the effect of different human fluids. We observed a significant increase in transformation frequencies in the presence of pleural fluid, whole blood cells and liquid ascites, and to a lesser extent with urine. The observed effects correlate with both HSA and bacterial content found in the assayed patient fluids. Taken together, these results are in agreement with our previous findings that highlight HSA as a possible host signal with the ability to trigger natural transformation in A. baumannii.