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The larger number of models of asteroid shapes and their rotational states derived by the lightcurve inversion give us better insight into both the nature of individual objects and the whole asteroid population. With a larger statistical sample we can study the physical properties of asteroid populations, such as main-belt asteroids or individual asteroid families, in more detail. Shape models can also be used in combination with other types of observational data (IR, adaptive optics images, stellar occultations), e.g., to determine sizes and thermal properties. We use all available photometric data of asteroids to derive their physical models by the lightcurve inversion method and compare the observed pole latitude distributions of all asteroids with known convex shape models with the simulated pole latitude distributions. We used classical dense photometric lightcurves from several sources and sparse-in-time photometry from the U.S. Naval Observatory in Flagstaff, Catalina Sky Survey, and La Palma surveys (IAU codes 689, 703, 950) in the lightcurve inversion method to determine asteroid convex models and their rotational states. We also extended a simple dynamical model for the spin evolution of asteroids used in our previous paper. We present 119 new asteroid models derived from combined dense and sparse-in-time photometry. We discuss the reliability of asteroid shape models derived only from Catalina Sky Survey data (IAU code 703) and present 20 such models. By using different values for a scaling parameter cYORP (corresponds to the magnitude of the YORP momentum) in the dynamical model for the spin evolution and by comparing synthetics and observed pole-latitude distributions, we were able to constrain the typical values of the cYORP parameter as between 0.05 and 0.6.

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation. Chimeric antigen receptor T (CAR-T) cells represent a breakthrough in the treatment of haematopoietic malignancies, however, in solid tumours this form of immune therapy is hampered by the scarcity of suitable targets showing high level tumour-restricted expression. Here authors generate CAR-T cells that target an osteosarcoma-specific isoform of alkaline phosphatase and show efficacy in orthotopic animal models while sparing healthy tissues.

The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.

HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell–based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2–negative donors as tools to detect HLA-A2–bound peptides from two leukemia-associated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide–HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide- and HLA-specific and responded strongly to HLA-A2–positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T-cell repertoires.

The possibility that allogeneic T cells may be targeted to leukemia has important therapeutic implications. As most tumor antigens represent self-proteins, high-avidity tumor-specific T cells are largely deleted from the repertoire of the patient. In contrast, T cells from major histocompatibility complex (MHC)-mismatched donors provide naïve repertoires wherein such cells have not been systematically eliminated. Yet, evidence for peptide degeneracy or poly-specificity warrants caution in the use of foreign human leukocyte antigen (HLA) or peptide complexes as therapeutic targets. Here, we cocultured HLA-A * 0201-negative T cells with autologous dendritic cells engineered to present HLA-A * 0201 complexed with a peptide from the B cell antigen CD20 (CD20p). HLA-A * 0201/CD20p pentamer-reactive CD8 + T cells were readily obtained from all donors. The polyclonal cells showed exquisite peptide and MHC specificity, and efficiently killed HLA-A * 0201-positive B cells, including primary chronic lymphocytic leukemia cells. The T cell receptor (TCR) sequences displayed a novel type of conservation, with extensive homology in the TCR β chain complementarity-determining region 3 and in J, but not V, region. This is surprising, as the donors were HLA disparate and their TCR repertoires are expected to show little overlap. The results demonstrate the first public recognition motif for an allogeneic HLA/peptide complex. The allo-restricted T cells or TCRs could provide graft-versus-leukemia in the absence of graft-versus-host disease.

While the risks of pedicle screw insertion are well established, there is a paucity of reports on complications associated with implant removal. We report two cases of acute osteoporotic vertebral compression fractures of the instrumented vertebral body adjacent to the fractured vertebra due to removal of pedicle screws in two female patients previously treated for vertebral lumbar burst fractures. Both patients had experienced only mild occasional pain at the thoracolumbar junction prior to the removal of the implants. In the formerly almost asymptomatic individuals, the acute osteoporotic fractures led to persistent severe back pain despite prolonged intensive treatment. Patients must be thoroughly informed of the rare but potential risks of spinal implant removal, particularly in cases of osteoporosis. We therefore do not recommend removal of spinal implants unless there are clear clinical indications for implant removal.

The OPERA experiment, designed to conclusively prove the existence of \\(\\rm \\nu_\\mu \\to \\nu_\\tau\\) oscillations in the atmospheric sector, makes use of a massive lead-nuclear emulsion target to observe the appearance of \\(\\rm \\nu_\\tau\\)'s in the CNGS \\(\\rm \\nu_\\mu\\) beam. The location and analysis of the neutrino interactions in quasi real-time required the development of fast computer-controlled microscopes able to reconstruct particle tracks with sub-micron precision and high efficiency at a speed of 20 cm^2 / h. This paper describes the performance in particle track reconstruction of the European Scanning System, a novel automatic microscope for the measurement of emulsion films developed for OPERA.

This paper describes the recent development of a novel automatic computer-controlled manipulator for emulsion film placement and removal at the microscope object table (also called stage). The manipulator is designed for mass scanning of emulsion films for the OPERA neutrino oscillation experiment and provides emulsion changing time shorter than 30 seconds with an emulsion film positioning accuracy as good as 20 microns RMS.

The use of nuclear emulsions in very large physics experiments is now possible thanks to the recent improvements in the industrial production of emulsions and to the development of fast automated microscopes. In this paper the hardware performances of the European Scanning System (ESS) are described. The ESS is a very fast automatic system developed for the mass scanning of the emulsions of the OPERA experiment, which requires microscopes with scanning speeds of about 20 cm^2/h in an emulsion volume of 44 micron thickness.