Advances in monotherapy and combination therapy of S-1 for patients with advanced non-small cell lung cancer: a narrative review.

Background and Objective: Both domestically and worldwide, non-small cell lung cancer (NSCLC) remain the leading cause of cancer-related death. As a fluorouracil derivative, S-1 which shows good efficacy and with few adverse effects have been widely confirmed in many solid tumors that it can provide a glimmer of hope for advanced NSCLC patients. We performed a review to explore the results of previous clinical studies of S-1 monotherapy as well as combined therapy involving S-1 in patients with advanced NSCLC. Methods: A literature search was conducted in Medline and PubMed databases using the keywords "S-1" AND "Advanced lung cancer" OR "Pharmacological mechanism". Key Content and Findings: A number of phase II clinical studies have reported on the favorable efficacy and excellent safety profiles of S-1 monotherapy in first-line or in posterior-line treatment for advanced NSCLC. In regard to S-1 in combination with chemotherapy, a number of phase II/III clinical studies have found the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of these regimens are similar to or better than immunological monotherapy with fewer adverse effects. In the case of S-1 combined with anti-vascular therapy, a number of phase II single-arm clinical studies have found that S-1 combined with bevacizumab, anlotinib and apatinib in advanced NSCLC, exhibits higher antitumor activity, less adverse effects for patients with advanced NSCLC. A phase II single-arm clinical study of gefitinib combined with S-1 had the ORR of 85.7% in the first-line treatment of advanced NSCLC. As for the combination of S-1 and immunotherapy, preliminary results of a phase II retrospective clinical trial demonstrated that the ORR was significantly better with S-1 sequential after immune checkpoint inhibitors (ICIs) than with S-1 alone. Conclusions: The findings indicate promising effectiveness and minimal toxicity with S-1 monotherapy and S-1 containing combined therapy in patients with advanced NSCLC to provide a potential treatment option for advanced NSCLC.

Circulating tumor DNA serial monitoring of relapse and responses to tislelizumab immunotherapy as second­line monotherapy for metastatic esophageal squamous cell carcinoma: A prospective study.

Anti-programmed cell death 1 immuno-monotherapy has become the second-line standard treatment for advanced esophageal squamous cell carcinoma (ESCC) after the failure of first-line chemotherapy. However, new biomarkers are still needed to identify patients at risk of tumor progression and to select patients with advanced ESCC who are likely to benefit from immunotherapy. A total of 12 patients with advanced ESCC treated with tislelizumab were prospectively enrolled and endoscopic biopsy samples were collected. Plasma was obtained prior to and after every 2-3 treatment cycles with tislelizumab and when disease progression occurred. Targeted sequencing of 425 genes from plasma cell-free DNA, DNA from leukocytes and fixed esophageal tumor biopsies was performed. The patients underwent imaging analyses every 6-8 weeks until disease progression. The association between status of circulating tumor DNA (ctDNA) or changes in ctDNA following tislelizumab immunotherapy and response, tumor progression and survival was determined. All patients had evaluable next-generation sequencing results at the time of analysis. The results showed that patients with ESCC with liver metastasis had a significantly shorter median progression-free survival (mPFS: 1.4 vs. 11.7 months; P=0.037). TSC complex subunit 2 [11.7 months vs. not reached (NR); P=0.004] and zinc finger protein 217 (11.7 months vs. NR; P=0.022) gene mutations were the independent and negative prognostic factors for median overall survival (OS), respectively. Of note, ctDNA dynamic changes expressed as ∆ mutant molecules per milliliter of plasma (∆MMPM; MMPM detected at the first monitoring time-point after the first infusion of tislelizumab as baseline MMPM) predicted progression-free survival (PFS) and OS more accurately compared to the ctDNA change of an individual gene. ∆MMPM <20% was an independent predictor of PFS (2.8 vs. 14.6 months; P=0.029), although there was no significant difference for OS (16.7 vs. 17.6 months; P=0.830). In conclusion, changes in ctDNA levels were associated with anti-tumor effects, progression and disease-specific survival. ctDNA sequencing is promising for predicting response and progression after tislelizumab immunotherapy as second-line monotherapy for advanced ESCC [the present study was part of the RATIONALE-302 study (ClinicalTrials.gov identifier no. NCT03430843; 29.01.2018)].

Efficient Catalysis of Ultrathin Two-Dimensional Fe2 O3 -CoP Heterostructure Nanosheets for Polysulfide Redox Reactions.

The "shuttle effect" and slow redox reactions of Li-S batteries limit their practical application. To solve these problems, a judicious catalyst design for improved battery cycle life and rate performance is essential. Herein, this issue is addressed by modifying the Li-S battery separator using a 2D Fe2 O3 -CoP heterostructure that combines the dual functions of polar Fe2 O3 and high-conductivity CoP. The synthesized ultrathin nanostructure exposes well-dispersed active sites and shortens the ion diffusion paths. Theoretical calculations, electrochemical tests, and in situ Raman spectroscopy measurements reveal that the heterostructure facilitates the inhibition of polysulfide shuttling and enhances the electrode kinetics. A sulfur cathode constructed using the Fe2 O3 -CoP-based separator provides an astonishing capacity of 1346 mAh g-1 at 0.2 C and a high capacity retention of ≈84.5%. Even at a high sulfur loading of 5.42 mg cm-2 , it shows an area capacity of 5.90 mAh cm-2 . This study provides useful insights into the design of new catalytic materials for Li-S batteries.

Efficacy and outcome analysis: Combination of Endostar and chemotherapy as a neoadjuvant treatment of stage IIIA/IIIB squamous cell lung cancer.

Patients with stage IIIA/IIIB squamous non-small cell lung cancer (SqCLC) are particularly challenging to treat with a poor 5-year survival rate and new treatment strategies are needed. In the present study, a retrospective, single-center study was conducted to explore the efficacy and safety of Endostar combined with chemotherapy as the neoadjuvant treatment in patients with stage IIIA/IIIB SqCLC. A total of 27 patients with locally advanced SqCLC treated with Endostar combined with chemotherapy as neoadjuvant therapy from January 1, 2017 to December 31, 2019 at the Zhejiang Cancer Hospital (Hangzhou, China) were included. Short-term efficacy, rate of surgical resection, long-term outcome and adverse events were analyzed. After treatment with Endostar combined with chemotherapy, 37% of the patients underwent surgery and the radical resection rate was 90%. The objective response rate was 63% for the total population and 80% for patients who received surgery. Of note, 100% of the patients achieved disease control after treatment with Endostar combined with chemotherapy. In patients who underwent surgical resection, postoperative pathology showed that 100% of the patients achieved pathological downstaging. Furthermore, 1 (10%) patient showed a pathological complete response after surgery. The median progression-free survival was 13.5 months and overall survival was 27.9 months for the total cohort. The most common adverse events (AEs) were anemia (69.4% of patients), followed by hypertension (29.6% of patients). Most of the AEs were grade 1-2 and only 4 patients (14.8%) developed grade 3-4 AEs. Endostar combined with chemotherapy was well-tolerated and showed promising efficacy in patients with stage IIIA/IIIB SqCLC. Further prospective studies are warranted to explore its value as a neoadjuvant therapy.

A novel sulfur@void@hydrogel yolk-shell particle with a high sulfur content for volume-accommodable and polysulfide-adsorptive lithium-sulfur battery cathodes.

High-energy-density secondary batteries are required for many applications such as electric vehicles. Lithium-sulfur (Li-S) batteries are receiving broad attention because of their high theoretical energy density. However, the large volume change of sulfur during cycling, poor conductivity, and the shuttle effect of sulfides severely restrict the Li-storage performance of Li-S batteries. Herein, we present a novel core-shell nanocomposite consisting of a sulfur core and a hydrogel polypyrrole (PPy) shell, enabling an ultra-high sulfur content of about 98.4% within the composite, which greatly exceeds many other conventional composites obtained by coating sulfur onto some hosts. In addition, the void inside the core-shell structure effectively accommodates the volume change; the conductive PPy shell improves the conductivity of the composite; and PPy is able to adsorb polysulfides, suppressing the shuttle effect. After cycling for 200 cycles, the prepared S@void@PPy composite retains a stable capacity of 650 mAh g-1, which is higher than the bare sulfur particles. The composite also exhibits a fast Li ion diffusion coefficient. Furthermore, the density functional theory calculations show the PPy shell is able to adsorb polysulfides efficiently, with a large adsorption energy and charge density transfer.

Rhodium-Catalyzed Generation of Anhydrous Hydrogen Iodide: An Effective Method for the Preparation of Iodoalkanes.

The preparation of anhydrous hydrogen iodide directly from molecular hydrogen and iodine using a rhodium catalyst is reported for the first time. The anhydrous hydrogen iodide generated was proven to be highly active in the transformations of alkenes, phenyl aldehydes, alcohols, and cyclic ethers to the corresponding iodoalkanes. Therefore, the present methodology not only has provided convenient access to anhydrous hydrogen iodide but also offers a practical preparation method for various iodoalkanes in excellent atom economy.

Iridium-Catalyzed Anti-Stereoselective Asymmetric Ring-Opening Reactions of Azabenzonorbornadienes with Carboxylic Acids.

The first anti-stereoselective asymmetric ring-opening reactions of azabenzonorbornadienes with carboxylic acids have been realized with an iridium catalyst assisted by nBu4NBr. The reaction features broad substrate scope and good functional group tolerance and allows the synthesis of chiral dihydronaphthalene derivatives with high optical purities.

Porous and single-crystalline ZnO nanobelts: fabrication with annealing precursor nanobelts, and gas-sensing and optoelectronic performance.

Porous and single-crystalline ZnO nanobelts have been prepared through annealing precursors of ZnSe · 0.5N2H4 well-defined and smooth nanobelts, which have been synthesized via a simple hydrothermal method. The composition and morphology evolutions with the calcination temperatures have been investigated in detail for as-prepared precursor nanobelts, suggesting that they can be easily transformed into ZnO nanobelts by preserving their initial morphology via calcination in air. In contrast, the obtained ZnO nanobelts are densely porous, owing to the thermal decomposition and oxidization of the precursor nanobelts. More importantly, the achieved porous ZnO nanobelts are single-crystalline, different from previously reported ones. Motivated by the intrinsic properties of the porous structure and good electronic transporting ability of single crystals, their gas-sensing performance has been further explored. It is demonstrated that porous ZnO single-crystalline nanobelts exhibit high response and repeatability toward volatile organic compounds, such as ethanol and acetone, with a short response/recovery time. Furthermore, their optoelectronic behaviors indicate that they can be promisingly employed to fabricate photoelectrochemical sensors.

Erlotinib plus capecitabine as first-line treatment for older Chinese patients with advanced adenocarcinoma of the lung (C-TONG0807): an open-label, single arm, multicenter phase II study.

Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma. This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1-14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry. In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7). This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.

[Efficacy of crizotinib for 28 cases of advanced ALK-positive non-small cell lung cancer].

OBJECTIVE: This study aims to evaluate the efficacy and safety of crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) patients. METHODS: Twenty-eight patients with advanced ALK-positive NSCLC were given orally crizotinib 250 mg b. i.d., and were followed up to evaluate the therapeutic efficacy and safety. RESULTS: Among the 28 patients, the objective response rate (ORR) was 71.4% (20/28) and disease control rate (DCR) was 92.9% (26/28). Three patients achieved complete response. Seventeen patients had partial response. The most common drug-related adverse events were mild flickering vision and gastrointestinal reaction. Eleven patients experienced flickering vision. Nine patients had nausea and vomiting. Eight patients had diarrhea. They were all reversible and of grade I or II. Only one patient had grade III myelosuppression. Among the 28 patients, 16 cases were disease-free and 12 cases had progressive disease, with a progression-free survival of 8.2 months. CONCLUSIONS: Crizotinib is effective and tolerable in the treatment of advanced ALK-positive NSLCC. However, its long-term treatment efficacy requires to be further studied.

Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9) polymorphisms are associated with NSCLC risk in a Chinese population.

Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9) encodes a plasma membrane protein of divalent cation channels and is expressed in keratinocytes. This study aimed to investigate CHRNA9 single-nucleotide polymorphisms (SNPs) for association with non-small cell lung cancer (NSCLC), especially squamous cell carcinoma (SCC) risk, in a Chinese population. This case-control study included 500 NSCLC patients and 500 age-matched healthy controls. CHRNA9 rs56159866, rs6819385, rs55998310, and rs182073550 SNPs were genotyped and associated for NSCLC risk by computing the odds ratios (ORs) and 95 % confidence intervals (CIs) from multivariate unconditional logistic regression analyses with adjustment for age. The frequencies of the CHRNA9 rs6819385 G allele were 16.1, 15.2, and 20.8% in male NSCLC patients, male SCC patients, and male controls, respectively. The CHRNA9 rs6819385 A allele was associated with an increased risk of developing NSCLC (P = 0.04, OR = 1.37; 95% CI 1.02-1.83) and SCC (P = 0.04, OR = 1.47; 95% CI 1.01-2.13). The CHRNA9 rs6819385 A/A homozygote was associated with an increased risk of NSCLC and SCC in all patients (OR = 1.38; 95% CI 1.06-1.79; P = 0.02, and OR = 1.61; 95% CI 1.09-2.38; P = 0.02, respectively) and in male patients (OR = 1.57; 95% CI 1.11-2.21; P = 0.01, and OR = 1.70; 95% CI 1.11-2.61; P = 0.01, respectively), indicating that the CHRNA9 rs6819385 A/A homozygote had a 1.61-fold and 1.70-fold increased risk of developing lung SCC in all patients (95% CI 1.09-2.38, P = 0.02) and in males (95% CI 1.11-2.61, P = 0.01), respectively. The CHRNA9 rs6819385 SNP was significantly associated with an increased risk of NSCLC, especially for SCC in male patients in this Chinese population.

[Analysis of the efficacy and survival of third-line treatment in advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: The appearance of highly effective and low toxic drugs enables an increasing number of advanced non-small cell lung cancer (NSCLC) patients to receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study respectively explores the efficacy and safety of single chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and doublet chemotherapy in advanced NSCLC third-line treatment. METHODS: This study included 115 NSCLC patients in the stage IIIb or IV who were retrospectively reviewed to investigate the differences of survival time between different treatments. Univariate and multivariate analyses were conducted based on the Kaplan-Meier method and Cox proportional-hazards model. RESULTS: The median progression free survival (PFS) values in the single agent, EGFR-TKIs and doublet groups were 2.30, 3.17 and 2.37 months, respectively (P=0.045). The median overall survival from the initiation of the third-line treatment were 8.00, 10.40 and 7.87 months in the three groups (P=0.110). The rates of stage III-IV toxicities were 33.3%, 18.2% and 68.8% (P<0.001), respectively. After the third-line treatment, the PFS was significantly increased in patients with a performance status (PS) of 0 to 1 (P<0.001), and the survival time was prolonged in patients who never smoke (P=0.011), have good PS (P<0.001), and have disease control after both first- and second-line treatments (P=0.044) using multivariate analysis. CONCLUSION: Advanced NSCLC patients who never smoke, have good PS scores, and have good disease control from the first- and second-line therapies could benefit more in third-line treatment. EGFR-TKIs therapy showed increased PFS compared with single and doublet agents.

Association between C3orf21, TP63 polymorphisms and environment and NSCLC in never-smoking Chinese population.

Recently, two genome-wide association studies in Asia identified gene polymorphisms known as rs4488809, rs9816619 in TP63 and rs2131877, rs952481 in C3orf21. It has been proposed that these polymorphisms are susceptibility loci for non-small cell lung cancer (NSCLC) development among Japanese and Korean populations. We ask whether susceptibility to NSCLC is limited to the Chinese population or whether the environment also affects genetic polymorphisms. We conducted a matched case-control study to explore this question. Results show that polymorphism of TP63 was not associated with NSCLC development, whereas variant genotypes of C3orf21 were nominally associated with a reduced risk of lung adenocarcinoma (OR=0.619, 95% CI=0.390-0.976). These results strongly suggest that environmental agents interact with human genetic polymorphism independent of ethnic background. In addition, the C3orf21 gene may be a potential susceptibility marker for lung adenocarcinoma independent of ethnic background and environmental agents.

[Efficacy study of single-agent gemcitabine versus gemcitabine plus carboplatin in untreated elderly patients with stage IIIb/IV non-small-cell lung cancer].

OBJECTIVE: To explore a chemotherapeutic regimen suitable for non-small cell lung cancer (NSCLC) in elderly patients. METHODS: A total of 68 elderly patients with NSCLC (stage IIIb/IV) were equally and randomly divided into single-agent and combined groups. Patients in single-agent group received gemcitabine 1000 mg/m(2) at Days 1 and 8 for a 21-day cycle. Those in combined group received gemcitabine 1000 mg/m(2) at Days 1 and 8 in combination carboplatin AUC5 at Day 2 for a 21-day cycle. The drugs were intravenously administered. All patients received 3 cycles of treatment. RESULTS: In single-agent and combined groups, CR 1 and 1, PR 12 and 13, response rates 38% and 41% were respectively observed. There was no statistically significant difference between two groups (P > 0.05). The 1-year and 2-year survival rates of single-agent and combined groups were 31% vs 32% and 12% vs 14% with a median survival of 9.9 and 9.8 months without a statistically significant difference (P > 0.05). The rates of leucopenia and thrombocytopenia (III-IV degree) were 47% and 38% in combined group and they were higher than 24% and 15% in single-agent group with a statistically significant difference (P < 0.05). The observer scale of lung cancer symptom scale showed that the post-treatment scores of appetite, fatigue and pain significantly improved in single-agent group while no improvement was observed in combined group. Also the scores of appetite, fatigue and pain of single-agent group were higher than those of combined group after chemotherapy (P < 0.05). CONCLUSION: Single-agent gemcitabine regimen is more suitable for advanced NSCLC in elderly patients.

Fabrication of the nanogapped gold nanoparticles film for direct electrical detection of DNA and EcoRI endonuclease.

In situ seeding growth of gold nanoparticles (AuNPs) by the reaction of HAuCl4 and NH2OH has been employed in the fabrication of the nanogapped AuNPs film for direct electrical detection of DNA hybridization and DNA cleavage by EcoRI endonuclease. The distance between neighboring gold nanoparticles is less than the length of the probe DNA, implying that the DNA strand could bridge the AuNPs to provide an electron tunneling path between microelectrodes. The double-stranded DNA (dsDNA) formed by hybridization of probe and target DNA is detected by current-voltage (I-V) curve measurements. When dsDNA is cleaved by restriction endonuclease EcoRI, the electron tunneling path can be cut off, which is reflected from the different slopes of I-V curves between dsDNA and dsDNA cleavage by EcoRI in the label-free electrical measurements. The novel and simple method of fabricating the nanogapped AuNPs film by in situ seeding growth could provide a promising bioanalytical platform for studying both DNA-DNA and DNA-protein interactions.

[The killing effect of rmhTNF-alpha combined with gemcitabine on human lung adenocarcinoma cells A549.].

BACKGROUND: At present clinical researches has proven that the chemotherapeutic effect on advanced non-small cell lung cancer (NSCLC) has gotten to plateau. Biotherapy combined with chemotherapy could improve curative effect on advanced NSCLC obviously. The project is aiming at exploring the killing effect and the mechanism of rmhTNF-alpha in combination with gemcitabine on human lung adenocarcinoma cell line A549. METHODS: CCK-8 was used to detect the inhibition ratio of rmhTNF-alpha and gemcitabine cell line A549; cell curve of growth was used to illustrate the influence of rmhTNF-alpha and gemcitabine on the proliferation of A549; FCM was used to detect the cell cycle and the apoptosis ratio of cell line A549 treated with either rmhTNF-alpha or gemcitabine or those combined. The change in cellular morphology and cell ultramicromorphology was observed by light microscope and transmission electron microscope respectively. RESULTS: The result of CCK-8 and cell curve of growth demonstrated that rmhTNF-alpha not only inhibited the proliferation of A549, but also enhanced the killing effect of gemcitabine; FCM showed that rmhTNF-alpha promoted S cell cycle arrest and reduced proportion of G2/M cell arrest; also showed different apoptosis ratio was most significant in the group of rmhTNF-alpha combination with gemcitabine; the changes of morphology was observed obviously by light microscope and transmission electron microscope. CONCLUSIONS: rmhTNF-alpha enhances the the killing effect of gemcitabine on human lung adenocarcinoma cells A549 by inducing apoptosis and promoting cell cycle arrest.

Casein kinase 1alpha interacts with RIP1 and regulates NF-kappaB activation.

Tumor necrosis factor alpha (TNFalpha) triggers a signaling pathway converging on the activation of NF-kappaB, which forms the basis for many physiological and pathological processes. In a kinase gene screen using a NF-kappaB reporter, we observed that overexpression of casein kinase 1alpha (CK1alpha) enhanced TNFalpha-induced NF-kappaB activation, and a CK1alpha kinase dead mutant, CK1alpha (K46A), reduced NF-kappaB activation induced by TNFalpha. We subsequently demonstrated that CK1alpha interacted with receptor interacting protein 1 (RIP1) but not with TRADD, TRAF2, MEKK3, IKKalpha, IKKbeta, or IKKgamma in mammalian cells. RIP1 is an indispensable molecule in TNFalpha/NF-kappaB signaling. We demonstrated that CK1alpha interacted with and phosphorylated RIP1 at the intermediate domain. Finally, we showed that CK1alpha enhanced RIP1-mediated NF-kappaB activation. Taken together, our studies suggest that CK1alpha is another kinase that regulates RIP1 function in NF-kappaB activation.

The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation.

SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is a Src homology 2 (SH2) domain-containing adaptor expressed in T cells and natural killer cells. Its essential role in immune responses is underscored by the recent finding that mutations in SAP result in a rare but fatal X-linked lymphoproliferative disease (XLP). Although SAP is known to associate with SLAM-family receptors, the exact molecular mechanism by which SAP regulates lymphocyte signaling remains elusive. We here report that in T cells, SAP associates with the PAK-interacting exchange factor (PIX), a guanine nucleotide exchange factor (GEF) specific for Rac/Cdc42 GTPases. Moreover, SAP, PIX, and an activated form of Cdc42 form a complex in mammalian cells. We demonstrate that the SAP-PIX interaction is specific and is mediated by the C-terminal region of the SAP SH2 domain and the PIX SH3 domain. We further show that SAP is required for the recruitment of PIX to the SLAM-family receptors. Interestingly, overexpression of SAP, but not its homolog EAT-2, leads to a synergistic activation of nuclear factor of activating T cells (NFAT) in combination with a calcium signal in T cells. This SAP-mediated activation appears to be receptor-dependent and can be blocked by a dominant negative form of PIX. Taken together, our data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation.