The frequency of poor outcomes in relapsed leukemia patients underscores the need for novel therapeutic approaches. The Food and Drug Administration-approved immunosuppressant FTY720 limits leukemia ...progression by activating protein phosphatase 2A and restricting nutrient access. Unfortunately, FTY720 cannot be re-purposed for use in cancer patients due to on-target toxicity associated with S1P receptor activation at the elevated, anti-neoplastic dose. Here we show that the constrained azacyclic FTY720 analog SH-RF-177 lacks S1P receptor activity but maintains anti-leukemic activity in vitro and in vivo. SH-RF-177 was not only more potent than FTY720, but killed via a distinct mechanism. Phosphorylation is dispensable for FTY720's anti-leukemic actions. However, chemical biology and genetic approaches demonstrated that the sphingosine kinase 2 (SPHK2)-mediated phosphorylation of SH-RF-177 led to engagement of a pro-apoptotic target and increased potency. The cytotoxicity of membrane-permeant FTY720 phosphonate esters suggests that the enhanced potency of SH-RF-177 stems from its more efficient phosphorylation. The tight inverse correlation between SH-RF-177 IC
and SPHK2 mRNA expression suggests a useful biomarker for SH-RF-177 sensitivity. In summary, these studies indicate that FTY720 analogs that are efficiently phosphorylated but fail to activate S1P receptors may be superior anti-leukemic agents compared to compounds that avoid cardiotoxicity by eliminating phosphorylation.
Nutrient stress that produces quiescence and catabolism in normal cells is lethal to cancer cells, because oncogenic mutations constitutively drive anabolism. One driver of biosynthesis in cancer ...cells is the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Activating mTORC1 by deleting its negative regulator tuberous sclerosis complex 2 (TSC2) leads to hypersensitivity to glucose deprivation. We have previously shown that ceramide kills cells in part by triggering nutrient transporter loss and restricting access to extracellular amino acids and glucose, suggesting that TSC2-deficient cells would be hypersensitive to ceramide. However, murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death. Consistent with the observation that ceramide limits access to both amino acids and glucose, TSC2(-/-) MEFs also had a survival advantage when extracellular amino acids and glucose were both reduced. As TSC2(-/-) MEFs were resistant to nutrient stress despite sustained mTORC1 activity, we assessed whether mTORC1 signaling might be beneficial under these conditions. In low amino acid and glucose medium, and following ceramide-induced nutrient transporter loss, elevated mTORC1 activity significantly enhanced the adaptive upregulation of new transporter proteins for amino acids and glucose. Strikingly, the introduction of oncogenic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment most likely by increasing nutrient demand. These results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1-dependent translation facilitates the adaptive cellular response to nutrient stress.
Following the first science results of the LUX-ZEPLIN (LZ) experiment, a dual-phase xenon time projection chamber operating from the Sanford Underground Research Facility in Lead, South Dakota, USA, ...we report the initial limits on a model-independent nonrelativistic effective field theory describing the complete set of possible interactions of a weakly interacting massive particle (WIMP) with a nucleon. These results utilize the same 5.5 t fiducial mass and 60 live days of exposure collected for the LZ spin-independent and spin-dependent analyses while extending the upper limit of the energy region of interest by a factor of 7.5 to 270 keV. No significant excess in this high energy region is observed. Using a profile-likelihood ratio analysis, we report 90% confidence level exclusion limits on the coupling of each individual nonrelativistic WIMP-nucleon operator for both elastic and inelastic interactions in the isoscalar and isovector bases. Published by the American Physical Society 2024
Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1
CXCR5
Bcl6
CD4
T cells will differentiate into PD-1
CXCR5
Bcl6
GC-Tfh ...cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1
CXCR5
CD4
T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit
PD-1
CXCR5
CD4
T cells upregulate IL-7Rα to become CXCR5
CD4
T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1
CXCR5
CD4
T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.
Abstract
T follicular helper (Tfh) cells were discovered as CD4 +T cells in the B cell follicles that express CXCR5 and help germinal center (GC) B cell responses. However, it is not clear which PD-1 ...+CXCR5 +Bcl6 +CD4 +T cells will differentiate into PD-1 hiCXCR5 hiBcl6 hiGC-Tfh cells while the others have a different fate, nor is it clear how GC-Tfh cell differentiation is regulated. Here we report that the sustained Tigit expression in PD-1 +CXCR5 +CD4 +T cells marked the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit −PD-1 +CXCR5 +CD4 +T cells upregulated IL-7Ra to become CXCR5 +CD4 +T memory precursor/memory cells—with or without a CCR7 +(or CCR7 +CD62L +) central memory phenotype. Our study further shows that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. Mechanistically, we find that c-Maf exerted an important function in the pre- to GC-Tfh transition, and we have identified c-Maf downstream factor Plekho1 as a novel regulator that played a stage-specific role in GC-Tfh cell differentiation.
Operative manipulation during hepatic resection (HR) causes tumor cell shedding which is a factor in disease recurrence. Radiofrequency ablation (RFA) causes coagulative necrosis and was used to ...destroy the tumor before HR. We evaluated tumor necrosis and recurrence of hepatic malignancies treated by sequential RFA/HR. A retrospective review of patients treated with sequential RFA/HR from April 1999 to January 2002 was performed. A Radionics 500-kW RF generator was used to ablate lesions via H2O-cooled electrodes under ultrasound guidance. Segmental HR was performed after RFA. Resected specimens were reviewed with hematoxylin and eosin staining and for apoptosis. Patient follow-up ranged from 10 to 33 months with evaluation of salient clinical, radiologic, and laboratory parameters. Seven patients (four male and three female) ages 62.1 ± 10.3 years had sequential RFA/HR. Four patients had hepatocellular carcinoma (HCC) and three had colorectal metastases (CRm). The tumors were unifocal right-lobe lesions measuring 4.1 ± 0.9 cm with a resection margin of 0.4 to 2.5 cm. Extensive necrosis was noted but intact nests of tumor cells occurred in all specimens with minimal apoptosis. Three of seven patients (two HCC and one CRm) developed pulmonary metastases at 3 to 20 months with one HCC patient developing concurrent liver metastases. Two deaths occurred in the HCC group. Sequential RFA/HR may minimize local recurrence; however, the high incidence of pulmonary metastases raises concern of transvenous migration. The histologic findings demonstrate foci of intact tumor cells after RFA. Controlled study of additional patients with long-term follow-up is necessary to better understand these findings.
Acute liver failure has been reported as a frequent complication of transarterial chemoembolization (TACE). We prospectively evaluated the adverse effects and biochemical changes of TACE. From 10/95 ...to 9/96, 35 patients with hepatic malignancies were evaluated for TACE. Fifteen patients (9 male and 6 female) received 23 treatments. Ten of 15 patients had hepatocellular carcinoma, and 5 had metastatic tumors. Treatment exclusion criteria included advanced liver disease, hepatic vascular thrombosis, and severe comorbidity. TACE consisted of intra-arterial infusion of a mixture of doxorubicin, cisplatin, and mitomycin followed by embolization. Clinical symptoms and laboratory studies were monitored following treatment. Technical success was achieved in all patients. Adverse symptoms were transient, and most resolved within 1 week. Changes in hepatic, renal, and hematologic function were temporary and returned to pre-TACE levels by 1 month. None developed acute liver failure. The mean hospital stay was 3 days. Ten of 13 patients had a significant decrease in baseline tumor markers. The actual survival was 93 per cent with a median follow-up of 10 months. TACE can be performed safely in patients with hepatic tumors. The adverse effects can be anticipated and easily managed.
Gas-CT cisternography is a simple and accurate procedure for detection of small acoustic nerve tumors. Review of one of the largest series in a single institution found that 98% of the studies ...clearly showed the presence or absence of tumors. The diagnostic pitfalls of the small number of studies in which significant errors were made, or could have been made, are discussed. It is concluded that certain situations appear to call for extra caution: (a) when the filling defect does not show a convex surface, (b) when the amount of cisternal gas is marginal, and (c) when the canal is small. In such situations careful attention to details and healthy skepticism may avert potential errors.
BACKGROUND Historically, surgical correction has been the treatment of choice for benign biliary strictures (BBS). Self-expandable metallic stents (MSs) have been useful for inoperable malignant ...biliary strictures; however, their use for BBS is controversial and their natural history unknown. HYPOTHESIS To test our hypothesis that MSs provide only short-term benefit, we examined the long-term outcome of MSs for the treatment of BBS. Our goal was to develop a rational approach for treating BBS. DATA EXTRACTION Between July 1990 and December 1995, 15 patients had MSs placed for BBS and have been followed up for a mean of 86.3 months (range, 55-120 months). The mean age of the patients was 66.6 years and 12 were women. Stents were placed for surgical injury in 5 patients and underlying disease in 10 patients (lithiasis, 7; pancreatitis, 2; and primary sclerosing cholangitis, 1). One or more MSs (Gianturco-Rosch "Z" for 4 patients and Wallstents for 11 patients) were placed by percutaneous, endoscopic, or combined approaches. We considered patients to have a good clinical outcome if the stent remained patent, they required 2 or fewer invasive interventions, and they had no biliary dilation on subsequent imaging. DATA SYNTHESIS Metallic stents were successfully placed in all 15 patients, and the mean patency rate was 30.6 months (range, 7-120 months). Five patients (33%) had a good clinical result with stent patency from 55 to 120 months. Ten patients (67%) required more than 2 radiologic and/or endoscopic procedures for recurrent cholangitis and/or obstruction (range, 7-120 months). Five of the 10 patients developed complete stent obstruction at 8, 9, 10, 15, and 120 months and underwent surgical removal of the stent and bilioenteric anastomosis. Four of these 5 patients had strictures from surgical injuries. The patient who had surgical removal 10 years after MS placement developed cholangiocarcinoma. CONCLUSIONS Surgical repair remains the treatment of choice for BBS. Metallic stents should only be considered for poor surgical candidates, intrahepatic biliary strictures, or failed attempts at surgical repair. Most patients with MSs will develop recurrent cholangitis or stent obstruction and require intervention. Chronic inflammation and obstruction may predispose the patient to cholangiocarcinoma.Arch Surg. 2001;136:664-669-->
PDF
