α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFß antibody to promote durable rejection and immunity in squamous cell carcinomas.

BACKGROUND: Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFß signaling. METHODS: To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFß or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. RESULTS: We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFß monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFß, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFß antibody administration attenuates these effects. We show that α-TGFß acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFß acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. CONCLUSIONS: We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFß-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFß combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFß/α-PD-1 combination therapy (NCT02947165).

Structure and mechanical properties of poly(D,L-lactic acid)/poly(epsilon -caprolactone) blends.

A series of blends of the biodegradable polymers poly(D,L-lactic acid) and poly( epsilon -caprolactone) were prepared by varying mass fraction across the range of compositions. Tensile testing was performed at room temperature using an extensometer and the elastic modulus was calculated for each blend. The blends were also tested to failure, and the strain-at-failure and yield stress recorded. While the blend has been shown to have a lower critical solution temperature, the mechanical properties were insensitive to the annealing conditions. Scanning electron microscopy was used to characterize the blend microstructure and poor adhesion was observed at the interface between blend components. Differential scanning calorimetry was performed but the results were somewhat variable, indicating this blend may have complex phase behavior that depends sensitively on the method of preparation. However, nuclear magnetic resonance data indicate the two components are phase separated. A percolation model is used to explain the observed mechanical data and the results are consistent with the predictions of the Kerner-Uemura-Takayangi model. The results of these experiments demonstrate the utility of polymer blending in tuning material properties.

Dynamical spreading of asteroid families by the Yarkovsky effect.

The orbital distributions of prominent asteroid families are thought to be direct by-products of catastrophic disruption events among diameter D greater, similar 100 kilometer bodies. Ejection velocities derived from studying observed families, however, are surprisingly high compared with results from impact experiments and simulations. One way to resolve this apparent contradiction is by assuming that D less, similar 20 kilometer family members, since their formation, have undergone semimajor axis drift by the thermal force called the Yarkovsky effect. Interactions between drifting family members and resonances can also produce unique eccentricity and/or inclination changes. Together, these outcomes help explain (i) why families are sharply bounded by nearby Kirkwood gaps, (ii) why some families have asymmetric shapes, and (iii) the curious presence of family members on short-lived orbits.

Patrón gammagráfico en un caso de quiste de Tarlov / Scintigraphic pattern in a case of Tarlov cyst

Se presenta el caso de un hombre de 40 años enviado a nuestro departamento con clínica de dolor lumbar bajo y ciática, sin historia de traumatismo previo. Las pruebas de laboratorio presentaron valores normales, mientras que las radiografías simples mostraron una zona de rarefacción en sacro. Se realizó una gammagrafía ósea con 99mTc-MDP para el estudio de la zona lumbosacra. Las imágenes planares no mostraron signos patológicos. Las imágenes de SPECT revelaron un defecto de captación en el hemicuerpo derecho de la segunda vértebra sacra, sin que existiera incremento periférico de captación del trazador. En las posteriores RMN y mielografía realizadas se evidenció la presencia de un quiste perineural (quiste de Tarlov) como causa de la erosión vertebral (AU)

We report the case of a 40-year-old man remitted to our department with a history of lower back pain and sciatica with no history of trauma. The laboratory analyses showed normal values whereas plain radiographs showed a sacrum rarefaction area. A 99mTc-MDP bone scintigraphy was performed to evaluate the lumbosacral area. Planar images did not show any abnormality. SPECT images revealed photopenic abnormality in the second sacral vertebral right hemibody, with no peripherally increased radiotracer accumulation. Subsequent MRI and CT myelography demonstrated the nature of the photopenic area as secondary to vertebral erosion by sacral perineurial cyst (Tarlov cyst) (AU)

Extended use of cranial CT in the evaluation of patients with stroke and transient ischaemic attacks.

The hypothesis was explored that patterns of ischaemic brain damage shown by CT may be of greater value in estimating the relevance of angiographic stenosis in the carotico-vertebral arteries in some patients than presenting clinical features. Five angiographic and six CT abnormalities were defined and charted independently in a blinded manner in 312 patients whom clinical features and subsequent management were known. Charts were combined for statistical analysis. Statistically significant associations were found between two types of CT lesion and angiographic abnormalities, but these were present in only 18% of cases. The distribution of clinical features did not differ significantly within this subset compared to the whole population, from which it was concluded that the hypothesis was upheld. Furthermore significantly more patients in this subset were subjected to carotid endarterectomy, suggesting that management decisions may have been modulated by CT findings in some patients.

[Characteristics of fractures in complete dentures]. / Neke karakteristike lomova totalnih zubnih proteza.

The analysis of fractures of the acrylate complete denture was performed in 200 patients taking into account age of patients, duration of denture usage, localization of fracture, frequency of fracture, number of denture per patient, and the state of the opposite jaw. There were 71,5% males and 60% female patients with the age from 60 to 69 years. The use of denture ranged from 10 to 15 years and the incidence of fracture was the largest in the first five years of denture use. One to three fractures usually occurred. In the largest number of patients, even up to 54%, it was the second denture. The acrylate opposite jaw complete denture had 43,5% of patients.

[Analysis of the most common causes of failure in complete dentures]. / Analiza najcescih uzroka neuspjeha totalnih zubnih proteza.

The most frequent failures in complete denture construction are examined. All possible failures have been taken into con- been divided into 3 groups: failures in denture retention, in interocclusal relations and factors which are reducing denture stabilization. Failures in the lower complete denture retention with poor extension have been most frequently found (90% cases). Less frequent was poor extension of the upper complete denture. Disbalance such as excentric occlusion and articulation blocking have been frequently found. A sizable vertical occlusal dimension was also significant.