Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G
controls its cell membrane association and phosphorylation of ...Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.
CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity.
.
By using the machine learning of artificial intelligence to explore the application business opportunities of the Metaverse in the MMORPG (Massively Multiplayer Online Role-Playing Game) interactive ...game market, we study the supply and demand laws of buyers and sellers at the market economy level, future trends, and business opportunities. The feasibility of its new products and services is explored under a pragmatic, cooperative model of the game community platform “Key to the Desert” case for the application level and business opportunities of Taiwan’s Metaverse markets. Online and offline integration (OMO; Online Merge Offline), precision marketing, and the customer management data platform (Customer Data Platform) are also explored in the application business opportunities of the Metaverse market. By combining the NFT (Non-Fungible Token) Monopoly game and MMORPG interactive games, we study the laws of supply and demand of buyers and sellers at the market economy level to provide third-party payment, electronic payment, mobile payment, and other transaction method certifications such as NFT (Non- Fungible Token). We also evaluation the future and security issues of cryptocurrency.
Many people are concerned about how their personal data is used for online behavioral advertising (OBA). Ad targeting explanations have been proposed as a way to reduce this concern by improving ...transparency. However, it is unclear when and why people might want ad targeting explanations. Without this insight, we run the risk of designing explanations that do not address real concerns. To bridge this gap, we conducted a four-week, mixed-methods field study with 60 participants to understand when and why people want targeting explanations for the ads they actually encountered while browsing the web. We found that users wanted explanations for around 30% of the 4,251 ads we asked them about during the study, and that subjective perceptions of how their personal data was collected and shared were highly correlated with when users wanted ad explanations. Often, users wanted these explanations to confirm or deny their own preconceptions about how their data was collected or the motives of advertisers. A key upshot of our work is that one-size-fits-all approaches to ad explanations are likely to fail at addressing people's lived concerns about ad targeting; instead, more personalized explanations are needed.
e14515 Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. A leading approach to boost NK cell-mediated anti-tumor activity is via the ...adoptive transfer of ex vivo activated NK cells. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells by the recipient and ensure adequate cell delivery of the product cells to the target. However, lymphodepletion can negatively impact combination therapies where a robust T cell response is desired. SNK02 is a first-in-kind, cryopreserved allogeneic non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced on a large commercial scale. We hypothesized that higher doses of SNK02 (to overcome autodigestion) could be delivered frequently without the need for lymphodepletion and that it might demonstrate activity against solid tumors that have failed multiple prior standard-of-care treatment options. Methods: In this Phase 1 dose escalation study (NCT05990920), SNK02 was administered intravenously (IV) weekly for 8 consecutive weeks in patients with advanced solid tumors. The starting dose was 6 x 10 9 SNK02 cells. The primary endpoint was safety based on adverse events (AEs), vitals, laboratory tests, and physical exams. Results: As of Feb 1, 2023, 5 patients with advanced refractory solid tumors have been enrolled. Median age was 64 (range 44 – 71) and 3 were male. The subtypes were 1 leiomyosarcoma, 1 angiosarcoma, 1 endometrial adenocarcinoma, 1 undifferentiated pleomorphic sarcoma, and 1 colorectal adenocarcinoma. Four of five patients completed 8 cycles of SNK02. There was 1 death on study, which was deemed unrelated to the investigational product (IP). Out of the 36 doses administered through Cycle 8, there were 17 Grade 1, 3 Grade 2, and 1 Grade 3 adverse AEs related to IP. The Grade 3 AE of increased fatigue resolved after 1 day with no intervention required. Antibodies appeared to develop around cycle 5 and appeared to correlate with AEs. The best objective response of SD was demonstrated in 100% of patients that completed the 8 cycles. Conclusions: SNK02 was well tolerated as a monotherapy and appears to have some clinical activity against pretreated solid tumors despite the lack of lymphodepletion. SNK02 will continue to be studied as a monotherapy and in potential combination treatment regimens with monoclonal antibodies and immune checkpoint inhibitors. Clinical trial information: NCT05990920 .
Instant messaging (IM) communication has been widely studied due to its prevalence in our everyday communication. Numerous factors that contribute to (un)responsiveness have been identified. Yet an ...integrated view of the factors that influence IM responsiveness remains absent. This paper reports qualitative findings from interviews with 46 IM users, and identifies five main elements underlying IM users’ response decisions: response habits, need fulfillment, perceived obligation, perceived readiness/suitability, and pace/rhythm coordination. To the best of our knowledge, this is the first integrated view of the key elements underlying IM responsiveness. Among these elements, we particularly highlight that regarding the influence of contextual factors on IM responsiveness, what may matters more is IM users’ perceptions of their readiness and suitability of the contexts, rather than the contexts’ objective properties. We also uncovered pace/rhythm coordination as a crucial factor behind IM responsiveness, which has been little discussed in the literature. Responsiveness, as our findings show, was often not a consequence, but a manifestation, of users’ pursuit of specific responsiveness-related aims such as ongoing shaping and sustaining of a dyad’s pace and rhythm.
•IM responsiveness is linked to habit, need, obligation, perception, and coordination.•The impact of contextual factors on IM responsiveness is subjective and perceptual.•IM responsiveness often manifests as an intention to shape a communicative pattern.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged ...administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.
•Concomitant PI3Kδ and SYK inhibition resulted in treatment-emergent pneumonitis, necessitating early study termination.•Initial trials of novel combinations should use conservative designs that are focused on safety.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Misfolded protein deposits are known to illicit a cascade of autoreactive neuroinflammation and damage in Alzheimer’s disease (AD). It is clear that removing these proteins by themselves ...will not fully address this complex process. Natural Killer (NK) cells are an essential part of the innate immune system that have been shown pre‐clinically to slow progression of amyloid deposition as well as identify and eliminate autoreactive T‐cells and damaged neurons. SNK01 is a first‐in‐kind, autologous non‐genetically modified NK cell product with significant increased cytotoxicity and over 90% activating receptor expression that can be consistently produced from any donor. We hypothesize that SNK01 could be consistently produced from any advanced AD patient and that it would be safe and potentially beneficial.
Method
In this Phase 1 dose escalation study (NCT04678453), SNK01 was administered intravenously (IV) every three weeks for a total of 4 treatments using a 3+3 design in pts with advanced disease confirmed by complete evaluation including PET scan. The starting dose was 1×109 SNK01 cells and the highest dose was 4×109SNK01 cells. Primary endpoint was safety and secondary endpoints included changes in MMSE, immune cytokines, and CSF protein levels.
Result
As of January 1, 2023, 9 pts out of a proposed 12 with advanced PET scan confirmed Alzheimer’s disease have been enrolled. Median age is 79 (range 56 – 84) and five were female. Median MMSE baseline score was 14 (range 2 – 23). NK cells were successfully activated and expanded from every patient. No treatment related adverse events were observed. Two patients showed improvement in their MMSE at six‐months compared to their pre‐treatment baseline, three patients showed no deterioration in their MMSE at six‐months, two patients progressed but at a much slower rate than they previously had, and two patients did not return for their six‐month follow‐up.
Conclusion
SNK01 with high cytotoxicity and activating receptor expression can be consistently produced from patients with advanced AD. SNK01 was very safe and appears to have some clinical activity in advanced AD. This data warrants further investigation in a larger Phase II trial with a longer treatment dosing duration.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the ...hypoxia-activated prodrug TH-302 in patients with advanced solid tumors.
TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B).
Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m(2) in arm A and from 670 to 940 mg/m(2) in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m(2) in arm A; the MTD was 575 mg/m(2). In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m(2); the MTD was 670 mg/m(2). Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m(2). Stable disease was observed in arms A and B in 18 and 9 patients, respectively.
The MTD of TH-302 was 575 mg/m(2) weekly and 670 mg/m(2) every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated.
Conventional cameras capture images with limited depth of field and no depth information. Camera systems have been proposed that enable additional depth information to be captured with the image. ...These systems reduce the resolution of the captured image or result in reduced sensitivity of the lens. We demonstrate a camera that is able to capture extended depth of field images together with depth information at each single frame while requiring minimal impact on the physical design of the camera or its performance. In this paper we show results with a camera for mobile devices, but this technology (named dual aperture to recall the major change in the camera model) can be applied with even greater effect in larger form factor cameras.
PDF
