SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein ...with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. ...Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS-mutant cancer cells
and
using cell line xenografts and primary human tumors.
, sensitivity of KRAS-mutant cells toward the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are grown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids. This antitumor activity is also observed
in mouse models. Interrogation of the MAPK pathway in SHP099-treated KRAS-mutant cancer models demonstrated similar modulation of p-ERK and DUSP6 transcripts in 2D, 3D, and
, suggesting a MAPK pathway-dependent mechanism and possible non-MAPK pathway-dependent mechanisms in tumor cells or tumor microenvironment for the
efficacy. For the KRAS
MIAPaCa-2 model, we demonstrate that the efficacy is cancer cell intrinsic as there is minimal antiangiogenic activity by SHP099, and the effects of SHP099 is recapitulated by genetic depletion of SHP2 in cancer cells. Furthermore, we demonstrate that SHP099 efficacy in KRAS-mutant models can be recapitulated with RTK inhibitors, suggesting RTK activity is responsible for the SHP2 activation. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic framework for treating KRAS-mutant cancers with SHP2 inhibitors.
Visible Emission Line Coronagraph on Aditya-L1 Prasad, B. Raghavendra; Banerjee, Dipankar; Singh, Jagdev ...
Current science (Bangalore),
08/2017, Volume:
113, Issue:
4
Journal Article
Peer reviewed
Solar coronagraph mimics total solar eclipse by blocking the solar disk and enabling the observation of extended coronal atmosphere of the Sun. Visible Emission Line Coronagraph (VELC), on-board ...Aditya-L1 space mission, is an internally occulted solar coronagraph capable of simultaneous imaging, spectroscopy and spectro-polarimetry close to the solar limb. This payload is designed to study the coronal plasma and heating of the solar corona. Studying development, dynamics and origin of coronal mass ejections and measurement of coronal magnetic fields over active regions are other important science goals. VELC is designed to image the solar corona at 500 nm with an angular resolution of 5″ over a field of view (FOV) of 1.05–3 R0. It also facilitates simultaneous multi-slit spectroscopy at three emission lines, viz. Fe XIV (530.3 nm), Fe XI (789.2 nm) and Fe XIII (1074.7 nm) with a spectral resolution of 28, 31 and 202 mÅ/pixel respectively, over an FOV of 1.05–1.5 R0. The payload has a dual-beam spectro-polarimetry channel for magnetic field measurements at 1074.7 nm.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Implementation research with pre- and post-comparison was planned to improve the quality of evidence-based intrapartum care services in Indian medical schools. We present the baseline study results ...to assess the status of adherence to intrapartum evidence-based practices (IP-EBP) in study schools in 3 states in India and the perception of the faculty.
A concurrent mixed-methods approach was used to conduct the baseline assessment in 9 medical schools in Rajasthan, Gujarat, and Union Territory from October 2018 to June 2019. IP-EBP among pregnant women in uncomplicated first (n=135), second (n=120), and third stage (n=120) of labor were observed using a predesigned, pretested checklist quantitatively. We conducted in-depth interviews with 33 obstetrics and gynecology faculty to understand their perceptions of intrapartum practices. Quantitative data were analyzed using SPSS (version 22). COM-B (Capability, Opportunity, and Motivation Behavior) model was used to understand the behaviors, and thematic analysis was done for the qualitative data.
Unindicated augmentation of labor was done in 64.4%, fundal pressure applied in 50.8%, episiotomy done in 58.3%, and delivery in lithotomy position was performed in 86.7% of women in labor.
Intrapartum practices that are not recommended were routinely practiced in the study medical schools due to a lack of staff awareness of evidence-based practices and incorrect beliefs about their impact.
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