A PLC-γ1 Feedback Pathway Regulates Lck Substrate Phosphorylation at the T‑Cell Receptor and SLP-76 Complex

Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T-cell signaling pathway. While its functions as a regulator of both Ca²⁺ signaling and PKC-family kinases are well characterized, PLC-γ1’s role in the regulation of early T-cell receptor signaling events is incompletely understood. Activation of the T-cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck. To determine if PLC-γ1 contributes to the regulation of these feedback networks, we performed a quantitative phosphoproteomic analysis of PLC-γ1-deficient T cells. These data revealed a previously unappreciated role for PLC-γ1 in the positive regulation of Zap-70 and T-cell receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively regulated the phosphorylation of SLP-76-associated proteins, including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr¹⁹² phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck’s targeting, but not its kinase activity, is altered by PLC-γ1, possibly through Lck Tyr¹⁹² phosphorylation and increased association of the kinase with protein scaffolds SLP-76 and TSAd

Impact of a gene expression classifier on the long-term management of patients with cytologically indeterminate thyroid nodules

<p><b>Objectives</b>: The gene expression classifier (GEC, Afirma<a href="#FN0001" target="_blank"></a>) reclassifies as molecularly benign approximately one half of thyroid nodule fine-needle aspiration (FNA) biopsies with an initial indeterminate cytopathology diagnosis, facilitating clinical monitoring in lieu of diagnostic thyroid surgery. This study evaluated the long-term management patterns and thyroid surgery rates of GEC benign patients compared to a control group of cytopathology benign patients and also described the costs of thyroid surgery. <b>Methods</b>: This retrospective cohort study used laboratory test results linked to payer medical claims data. Patients who underwent FNA biopsy between 1 January 2011 and 31 July 2013 were selected. GEC benign patients were matched 1:3 to cytopathology benign patients on biopsy year, gender, nodule size and age. Outcomes measured included thyroid-related follow-up clinic visits, ultrasound examinations and surgeries. <b>Results</b>: Out of 2059 patients, matched groups consisting of 201 GEC benign patients and 603 cytopathology benign patients were evaluated over an average follow-up of 20 months. The proportions of GEC benign and cytopathology benign patients that underwent thyroid surgery (11.4% versus 10.1%, <i>p</i> = 0.594), and received a follow-up ultrasound exam (60.2% versus 61.7%, <i>p</i> = 0.706), respectively, were not significantly different. Average thyroid-related medical cost for the surgical episode and during 6 months following surgery were $10,432.00 (SD$8301) and $10,939.00 (SD$9656) respectively. <b>Limitations</b>: The study cohort included only patients whose diagnostic laboratory test results and administrative claims data were uniquely identifiable and could be linked on multiple identifiers; the rigorous matching and patient selection algorithms utilized improved the robustness and internal validity of the study. Claims were used as a proxy for clinical utilization without chart review confirmation. <b>Conclusion</b>: Patients with GEC and cytopathology benign diagnoses were managed similarly. The majority of patients in both groups did not undergo surgery and were managed with usual care, consisting of clinical follow-up and ultrasound exams.</p

Synthesis of Nonspherical Mesoporous Silica Ellipsoids with Tunable Aspect Ratios for Magnetic Assisted Assembly and Gene Delivery

Despite the extensive application of ellipsoidal micro-/nanoparticles, the synthesis of shape anisotropic ellipsoids is rare because of the minimization of surface free energy that favors simple spherical shape rather than complex nonspherical shape. We present the synthesis of silica ellipsoids with hexagonal mesostructure via the organic–inorganic cooperative assembly in the presence of cosolvents (KCl and ethanol). The aspect ratio of ellipsoids can be tuned systematically by controlling the concentration of ethanol. Transmission electron microscopy (TEM) shows that the ellipsoid possesses one-dimensional (1-D) pore channels parallel to the major axis, and the electron tomography (ET) technique shows that the ellipsoid has indeed hexagonal prism morphology in the middle and ellipsoidal morphology at two tips. A mechanism for the formation of mesoporous silica ellipsoids has been proposed. Importantly, magnetite/silica composite ellipsoids were prepared through a nanocasting route and can be used as building blocks to organize into ordered arrays in response to an external magnetic field. In addition, after functionalized with amino-groups, the amino-modified anisotropic magnetite/silica ellipsoids can be further used as carriers for delivering oligo-DNA-Cy3 into tumor cells, showing potential in directed self-assembly and drug/gene delivery

Synthesis of Nonspherical Mesoporous Silica Ellipsoids with Tunable Aspect Ratios for Magnetic Assisted Assembly and Gene Delivery

Despite the extensive application of ellipsoidal micro-/nanoparticles, the synthesis of shape anisotropic ellipsoids is rare because of the minimization of surface free energy that favors simple spherical shape rather than complex nonspherical shape. We present the synthesis of silica ellipsoids with hexagonal mesostructure via the organic–inorganic cooperative assembly in the presence of cosolvents (KCl and ethanol). The aspect ratio of ellipsoids can be tuned systematically by controlling the concentration of ethanol. Transmission electron microscopy (TEM) shows that the ellipsoid possesses one-dimensional (1-D) pore channels parallel to the major axis, and the electron tomography (ET) technique shows that the ellipsoid has indeed hexagonal prism morphology in the middle and ellipsoidal morphology at two tips. A mechanism for the formation of mesoporous silica ellipsoids has been proposed. Importantly, magnetite/silica composite ellipsoids were prepared through a nanocasting route and can be used as building blocks to organize into ordered arrays in response to an external magnetic field. In addition, after functionalized with amino-groups, the amino-modified anisotropic magnetite/silica ellipsoids can be further used as carriers for delivering oligo-DNA-Cy3 into tumor cells, showing potential in directed self-assembly and drug/gene delivery

Synthesis of Nonspherical Mesoporous Silica Ellipsoids with Tunable Aspect Ratios for Magnetic Assisted Assembly and Gene Delivery

Despite the extensive application of ellipsoidal micro-/nanoparticles, the synthesis of shape anisotropic ellipsoids is rare because of the minimization of surface free energy that favors simple spherical shape rather than complex nonspherical shape. We present the synthesis of silica ellipsoids with hexagonal mesostructure via the organic–inorganic cooperative assembly in the presence of cosolvents (KCl and ethanol). The aspect ratio of ellipsoids can be tuned systematically by controlling the concentration of ethanol. Transmission electron microscopy (TEM) shows that the ellipsoid possesses one-dimensional (1-D) pore channels parallel to the major axis, and the electron tomography (ET) technique shows that the ellipsoid has indeed hexagonal prism morphology in the middle and ellipsoidal morphology at two tips. A mechanism for the formation of mesoporous silica ellipsoids has been proposed. Importantly, magnetite/silica composite ellipsoids were prepared through a nanocasting route and can be used as building blocks to organize into ordered arrays in response to an external magnetic field. In addition, after functionalized with amino-groups, the amino-modified anisotropic magnetite/silica ellipsoids can be further used as carriers for delivering oligo-DNA-Cy3 into tumor cells, showing potential in directed self-assembly and drug/gene delivery

Image_1_PD-1 inhibitors plus anti-angiogenic therapy with or without intensity-modulated radiotherapy for advanced hepatocellular carcinoma: A propensity score matching study.pdf

BackgroundWhether intensity-modulated radiotherapy (IMRT) can enhance the efficacy of the programmed death (PD)-1 inhibitors combined with anti-angiogenic therapy for hepatocellular carcinoma (HCC) is unclear. Therefore, we conducted this multicenter retrospective study to investigate the efficacy of the combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT.MethodsFrom April 2019 to March 2022, a total of 197 patients with HCC [combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT (triple therapy group), 54; PD-1 inhibitors plus anti-angiogenic therapy (control group), 143] were included in our study. Propensity score matching (PSM) was applied to identify two groups with similar baselines. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) of the two groups were compared before and after matching.ResultsPrior to PSM, the triple therapy group had higher ORR (42.6% vs 24.5%, P = 0.013) and more superior median OS (mOS) (20.1 vs 13.3 months, P = 0.009) and median PFS (mPFS) (8.7 vs 5.4 months, P = 0.001) than the control group. Following PSM, the triple therapy group still exhibited better mPFS (8.7 vs 5.4 months, P = 0.013) and mOS (18.5 vs 12.6 months, P = 0.043) than the control group. However, the ORR of the two groups was similar (40% vs 25%, P = 0.152). No significant difference was observed in the treatment-related adverse events between the two groups (P ConclusionsThe combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT for HCC is a promising regimen.</p