Ideal Target For Treatment Research Articles

The promotion of cell proliferation and invasion in cutaneous squamous cell carcinomas after ARNT downregulation is associated with CXCL3

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor associated with adaptive responses to cellular stress. Its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. The aim of this study was to investigate the role of ARNT in cSCC. Immunohistochemistry revealed downregulation of ARNT in cSCC, precancerous lesions (actinic keratosis), and cells. Knockdown of ARNT in A431 and SCL-1 cells significantly enhanced cell growth and metastasis. Microarray analysis and Ingenuity Pathway Analysis confirmed that loss of ARNT in A431 cells was highly correlated with cell growth and movement and upregulated CXCL3 expression. Cellular and xenograft experiments further confirmed that ARNT regulates cSCC proliferation and invasiveness in a CXCL3-dependent manner. ARNT may regulate CXCL3 expression through ROS-STAT3 pathway. In conclusion, this study demonstrates that ARNT plays a critical role in the development of cSCC and significantly affects the proliferation and metastatic ability of cSCC cells. It has the potential to serve as an ideal treatment target for cSCC.

Preliminary exploration of Trop2 ADC in combination with immune checkpoint inhibitors in the different molecular subtypes of invasive breast carcinoma.

e12558 Background: Human trophoblastic cell surface antigen 2 (Trop2) is a transmembrane protein overexpressed in breast cancer tissues. However, it is present at minimal levels in adult somatic tissues, making it an ideal target for treatment with antibody-drug conjugates (ADCs). Sacituzumab govitecan, an anti-Trop2 ADC, has been approved for the treatment of triple-negative breast cancer and urothelial cancer. Recent studies have demonstrated that human cytotoxic T lymphocytes can recognize Trop2. Accordingly, we aimed to assess the role of Trop2 in the tumor immune activity of different subtypes of breast cancer, and laying the foundation for further studies on the efficacy of the combination of Trop2 ADC and immune checkpoint inhibitors in breast cancer. Methods: We retrospectively retrieved tissues from 152 invasive breast carcinoma of no special type and 111 benign breast tumor tissues and undergoing surgical resection at our institution from 2018 to 2023. Immunohistochemistry was used to detect Trop2 and PD-L1 expression and lymphatic invasion in patients, and their correlations with clinicopathological factors were analyzed. Trop2 expression was evaluated using the H-score. The median as the cut-off value, a score of 0–240 indicated low expression, and 240–300 indicated high expression. Cases with CPS ≥ 1% were considered positive for PD-L1. Results: The expression was Trop2 in breast cancer tissues than in benign tumor tissues (P<0.0001). Immune infiltration analysis suggested that Trop2 expression was correlated with immune cell infiltration and the abundance (P<0.001). Kaplan–Meier plotter analysis demonstrated that high Trop2 expression was related to poor prognosis in patients with triple-negative breast cancer (overall survival: HR=1.53, P=0.029; relapse-free survival: HR=1.26, P=0.045). In contrast, Trop2 expression was not significantly associated with prognosis in other breast cancer subtypes. However, there was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in breast cancer. Conclusions: The findings suggest that Trop2 correlates with poor prognosis and immune cell infiltration in breast cancer. This indicates the role of Trop2 as a potential prognostic biomarker, laying the foundation for further research focusing on the immune regulatory role of Trop2. [Table: see text]

Non-coding RNAs in cancer immunotherapy: A solution to overcome immune resistance?

With the rapid advancement in immunotherapy, cancer immune resistance has become more evident, which demands new treatment approaches to achieve greater efficacy. Non-coding RNAs (ncRNAs) are a heterogeneous group of RNAs that are not translated to proteins but instead regulate different stages of gene expression. Recent studies have increasingly supported the critical role of ncRNAs in immune cell-cancer cell cross-talk, and numerous ncRNAs have been implicated in the immune evasion of cancer cells. Cancer cells take advantage of ncRNAs to modulate several signaling pathways and upregulate the expression of immune checkpoints and anti-inflammatory mediators, thereby dampening the anti-tumor response of M1 macrophages, dendritic cells, cytotoxic T cells, and natural killer cells or potentiating the immunosuppressive properties of M2 macrophages, regulatory T cells, and myeloid-derived suppressive cells. Upregulation of immunosuppressive ncRNAs or downregulation of immunogenic ncNRAs is a major driver of resistance to immune checkpoint inhibitors, cancer vaccines, and other means of cancer immunotherapy, making ncRNAs ideal targets for treatment. In addition, ncRNAs released by cancer cells have been demonstrated to possess prognostic values for patients who undergo cancer immunotherapy. Future clinical trials are urged to consider the potential of ncRNAs in cancer immunotherapy.

KRAS mutation methylation clonality in early-stage pancreatic cancer.

614 Background: KRAS is mutated in 90% of pancreatic cancers making it a seemingly ideal target for treatment and yet, with the exception of the rare G12C mutation, KRAS is undruggable for the vast majority of pancreatic patients. Herein, we characterize, in silico, KRAS methylation-derived mutation clonal and subclonal diversity in PDAC and examine their impact upon clinical outcomes. Methods: We developed a mutation methylation (MM) clonality workflow for gene mutation assignment as clonal versus subclonal and applied it genome-wide to TCGA data. For comparison, we used the cancer cell fraction (CCF) clonality prediction. We examined clinical outcomes by comparing in months (mos), Kaplan-Meier estimated overall survival (OS) using a log-rank test and a cox model for testing several features. We performed differential gene expression, differential gene correlation, and gene set enrichment analyses (GSEA) between KRAS MM clonal versus subclonal early stage pancreatic patients. Results: Using 104 TCGA early stage pancreatic cancer patient tumors from TCGA with mutation, methylation and clinical outcomes data, we defined KRAS MM clonality (n = 70 clonal, n = 34 subclonal) and CCF clonality (n = 74 clonal, n = 28 subclonal) tumors. Clonality assignment between methods was 53% clonal and 17% subclonal concordant, and 19% discordant among samples. KRAS MM clonality was associated with significantly (p = 0.046) shorter OS (median OS = 11.5 mos) as compared to the KRAS subclonal group (median OS = 15 mos). By comparison, KRAS CCF clonal and subclonal patient groups did not differ in their OS. When RNA-Seq derived subtypes for pancreatic cancer were included in a model with our KRAS MM clonality marker, only our marker remained as significantly associated with OS. Median KRAS gene expression was significantly (p = 0.01) higher in the KRAS MM clonal versus subclonal group. A GSEA showed enrichment of MYC targets in the KRAS clonal group. We identified 72, mostly protein coding genes residing on chromosomes 5q, 7p and 8p that correlated with KRAS gene expression only in the subclonal group. Conclusions: Our analyses shows a potential clonality dissection of the established 90% KRAS mutation rate in pancreatic cancer, which based on our MM workflow, may be dissected into 61% KRAS clonal and 30% KRAS subclonal. By assigning clonality based on another DNA data type using CCF, we obtain 65% KRAS clonal and 25% KRAS subclonal. Thus, regardless of which DNA-based workflow, overall, the KRAS clonality rates are similar. There is a notable difference however in patient-level assignment of KRAS clonality as only our workflow showed poor OS associated with KRAS clonality. The introduction of a methylation-based mutation clonality marker could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for patient and treatment selection, and clinical trial monitoring of tumor responses.

The trough of disillusionment: A critique of the “transition” paradigm

I will attempt to address the issues surrounding the CHR concept in light of novel data and briefly discuss emerging alternatives. The root problem of the CHR early invention strategy is the exertion of reducing early nonspecific (pluripotent) psychopathology to a unidimensional model restricted only to positive psychotic symptoms, which define the binary categories of CHR and “transition” in help-seeking populations. This major conceptual handicap undermines the validity and clinical utility. The core predictor of the “transition” rate is the degree of the risk-enrichment and not the CHR status. Even with a significant pretest risk enrichment, the prognostic accuracy is mediocre. The incidence and “transition” rates of CHR in the community are very low; therefore, CHR does not represent a cost-effective clinical target—prevention paradox. CHR succeeding early pluripotent psychopathology is already late for intervention. “Transition” is not a categorical progression but a unidimensional shift in psychotic symptoms, and therefore, influenced by the fluctuation of psychotic symptoms, leading to both false positives and underestimation of nonpsychotic psychopathology. There exists no evidence for a specific effect of any intervention in preventing “transition”; therefore, CHR is not an ideal treatment target. Binary “transition” outcome does not represent a valid phenotype for research as “transition” rates are primarily driven by the sampling heterogeneity. The multidimensional psychopathology and functioning are more clinically relevant, overarching, and service-user-centered measures to define individual risk and outcome. Guided by the public health perspective, a universal early intervention framework, underscoring improved access to care, may represent a better strategy.DisclosureNo significant relationships.

Frequencies and predictors of the Lupus Low Disease Activity State and remission in treatment-naïve patients with systemic lupus erythematosus.

To evaluate the attainability of Lupus Low Disease Activity State (LLDAS) and definitions of remission in SLE (DORIS) in a treatment-naïve cohort of SLE. LLDAS5 was defined as LLDAS with a prednisone dose ≤5 mg/day. There were four definitions in DORIS: clinical remission on treatment (RONT), complete RONT, clinical remission off treatment (ROFT) and complete ROFT. The treatment-naïve patients from Peking University First Hospital SLE cohort were enrolled. The time to each state and their annual cumulative probabilities were estimated. The frequencies of patients who achieved each component of LLDAS or DORIS during follow-up were determined. The predictors of time to each state were identified. A total of 218 patients were included, with a median follow-up of 4.48 years. Respectively, 190 (87.2%), 160 (73.4%), 148 (67.9%), 94 (43.1%), 23 (10.6%) and 18 (8.3%) patients achieved LLDAS, LLDAS5, clinical RONT, complete RONT, clinical ROFT and complete ROFT. The median time to LLDAS, LLDAS5, clinical RONT and complete RONT were 1.4, 2.3, 2.6 and 4.7 years, respectively. Positive anti-dsDNA, RP and anaemia were significantly associated with prolonged time to LLDAS, LLDAS5 or clinical RONT. Our data confirmed that LLDAS is an attainable early treatment target for SLE. Though with more difficulty, RONT can be achieved in two-thirds of our patients. ROFT may not be an ideal treatment target at present as it is only attained in few patients.

Treat to target in systemic lupus erythematosus

For the first time, the European League Against Rheumatism (EULAR) recommendations for the management of systemic lupus erythematosus (SLE) include atreat to target (T2T) strategy, naming remission as the main target. The aim is to improve the long-term survival, prevent damage and optimize the health-related quality of life. Compared to rheumatoid arthritis (RA) for which the T2T approach is already widely used, establishing T2T in SLE remains challenging due to its heterogeneity and limited treatment options. The aim of this article is to outline the current status of the T2T concept for SLE and to identify challenges and particularities. A special focus is placed on the use of activity scores and the importance of steroids in targeted treatment of SLE. The use of T2T for SLE remains achallenge. With the definitions of the lupus low disease activity states (LLDAS) and the definitions of remission in SLE (DORIS) abig step forward has been taken on the road towards the ideal treatment target; however, many aspects of the "treat" remain unclear. As an example, due to alack of data there are no explicit strategies for steroid reduction although it is often mandatory to achieve the targets. The T2T also includes much more than only immunosuppressive treatment and antimalarial agents, as disease damage which has already occurred and damage due to drugs, concomitant phenomena (such as depression) and comorbidities as well as measures for secondary prophylaxis must also be included.

A phase II trial of durvalumab (Medi 4736) in advanced endometrial cancer: PHAEDRA.

TPS5614 Background: Advanced endometrial cancer (EC) progressing after 1 or more lines of chemotherapy is an area of unmet need with objective tumour response rates to subsequent lines of chemotherapy of ≤20%. DNA mismatch repair (MMR) deficiency, seen in approximately 15% of EC, is associated with a high mutational load and in addition, up to 90% of ECs are reported to have PDL1/ PD1 expressions. These factors make immune check point inhibition an ideal target for treatment. Methods: DESIGN: Multicentre phase 2 trial in two cohorts. ELIGIBILITY: Advanced, unresectable endometrial cancer that is either MMR-proficient and progressing after 1-3 lines of chemotherapy, or MMR-deficient and progressing after 0-3 lines of chemotherapy. ENDPOINTS: Objective tumour response rate (OTRR) according to iRECIST (primary) and RECIST 1.1, disease control rates at 16 and 24 weeks, progression free survival, overall survival, duration of OTR and DC, adverse events, health related quality of life. Tertiary correlative objectives: Associations between immunologic (including PD-L1), DNA mismatch repair (MMR) and other genetic characteristics with clinical outcomes; and family history of cancer and referral to familial cancer services. INTERVENTION: Durvalumab 1500 mg intravenously every 28 days until disease progression or prohibitive toxicity. STATISTICS: Total of 70 participants in two cohorts (35 each) will have 90% power to distinguish a difference in observed OTRR of ≥20% versus ≤5% (uninteresting rate) using Simon’s 2-stage minimax design with 10% type 1 error rate and allowing 10% ineligibility and missing data. Durvalumab will be considered worthy of pursuit if 4 or more OTR are observed in the first 32 participants in each cohort (OTRR ≥12.5%). BIOSPECIMENS: Tumour tissue and serial bloods (5 time points) will be collected for translational research. PHAEDRA is an investigator-initiated, cooperative-group trial led by ANZGOG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney. Australian New Zealand Clinical Trials Registry: Clinical trial information: ACTRN12617000106336.

Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs. The structure and activity relationship was also described. The best active and selective compound 5e inhibited PTP1B activity with an IC50 of 4.53μM. Molecular docking analysis further demonstrated that compound 5e bound to the active pocket of PTP1B. The results might provide some insights for further development of new drugs for type II diabetes and obesity.

Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a major health concern, with high rates of mortality and morbidity and no highly effective clinical interventions. Basic research in animal models of ICH has provided insight into its complex pathology, in particular revealing the role of inflammation in driving neuronal death and neurologic deficits after hemorrhage. The response to ICH occurs in four distinct phases: (1) initial tissue damage and local activation of inflammatory factors, (2) inflammation-driven breakdown of the blood-brain barrier, (3) recruitment of circulating inflammatory cells and subsequent secondary immunopathology, and (4) engagement of tissue repair responses that promote tissue repair and restoration of neurologic function. The development of CNS inflammation occurs over many days after initial hemorrhage and thus may represent an ideal target for treatment of the disease, but further research is required to identify the mechanisms that promote engagement of inflammatory versus anti-inflammatory pathways. In this review, the authors examine how experimental models of ICH have uncovered critical mediators of pathology in each of the four stages of the inflammatory response, and focus on the role of the immune system in these processes.

PTPS-21MAPK PATHWAY INHIBITOR THERAPY FOR PROGRESSIVE PEDIATRIC ASTROCYTOMAS

BACKGROUND: Brain tumors are the most common solid tumor in childhood and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The MAPK pathway, and more specifically, BRAF mutations have been shown to be prevalent in pediatric astrocytomas and may represent one such area to target. METHODS: We describe the clinical course of four cases of non-operable pediatric astrocytomas (Grade I or II) whose tumor progressed despite chemotherapy. Testing of each tumor showed BRAF mutations and each patient was started on either a BRAF inhibitor or MEK inhibitor. A review of each patient's medical record and imaging studies was completed. Tumor volumetrics were calculated prior to and after treatment. RESULTS: Three patients had optic pathway gliomas; two pilocytic astrocytomas (WHO Grade I) and one pilomyxoid astrocytoma (WHO Grade II). The fourth tumor was a thalamic infiltrating astrocytoma (WHO Grade II). Genetic testing showed a duplication of BRAF (7q34) in 3 tumors and treatment with a MEK inhibitor, trametinib, was initiated. One tumor was found to have a BRAF T1799A (V600E) point mutation and the patient was started on vemurafenib, a BRAF inhibitor. Duration of treatment to date ranged from 105 to 805 days. Pretreatment tumor volumes varied from 15.1cm3-451.8cm3. All four tumors had a decrease in volume (2.1cm3-227.2cm3, 13.5-80.6% decrease) on these inhibitors. CONCLUSION: We have shown in this small subgroup of patients that MEK inhibitors and BRAF inhibitors in tumors with BRAF mutations are effective in decreasing tumor volume in otherwise progressive pediatric astrocytomas. This would suggest these may be ideal targets for treatment of tumors with these mutations and that tumor volume measurement is a reasonable method for documenting response in this patient group.

Targeting Hsp90 in urothelial carcinoma.

Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

Bile acid receptors in non-alcoholic fatty liver disease

Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions.

Neurotrophic effects of 7,8-dihydroxycoumarin in primary cultured rat cortical neurons

Neuronal loss in the central nervous system is central to the occurrence of neurodegenerative diseases. Pharmaceutical companies have devoted much effort to developing new drugs against such diseases, since there are currently no effective drugs for neurodegenerative disease treatment. Promoting the capacity for nerve regeneration is an ideal treatment target. The present study aimed to investigate the neurotrophic effects of 7,8-dihydroxycoumarin (DHC) or daphnetin in primary cultured rat cortical neurons. Cortical neurons were identified by microtubule-associated protein 2 (MAP2) immunostaining. Morphological observation was used to measure the average length of neurite outgrowth. MTT and lactate dehydrogenase assays were used to assess neuronal survival. The mRNA expression of MAP2 and brain-derived neurotrophic factor (BDNF) was measured by RT-PCR. MAP2 immunostaining showed that most of the cultured cells were neurons. Compared with the vehicle control group, DHC promoted neurite outgrowth and prolonged neuronal survival time at concentrations ranging from 2 to 8 μmol/L. Expression of both BDNF mRNA and MAP2 mRNA was increased in the groups treated with 2, 4 and 8 μmol/L DHC. DHC significantly increases neurite outgrowth and promotes neuronal survival in primary cultured rat cortical neurons. The neurotrophic effects of DHC are probably associated with increased BDNF expression.

Abstract 3134: Integrin α6β4 upregulates EGFR ligands in pancreatic cancer cells

Abstract Because of late diagnosis and lack of effective treatments, pancreatic cancer is the 4th leading cause of cancer death in the US, with a death to incidence ratio that is nearly equal. In an effort to improve patient survival, there needs to be a focus on molecular mechanisms that confer a metastatic phenotype. The integrin α6β4 is overexpressed in pancreatic carcinoma and plays a role in cancer progression by promoting tumor invasion and metastasis as well as cell survival. We find that integrin α6β4 overexpression leads to upregulation of cancer promoting genes such as amphiregulin and epiregulin, ligands of the epidermal growth factor receptor (EGFR). The purpose of this study is to address how integrin α6β4 upregulates these ligands. We have identified large CpG islands within the amphiregulin and epiregulin promoters (-1500 to +500 bp from TSS) using CpG plot and CpG Island searcher. This provides a potential site for epigenetic modifications, which are essentially reversible, and therefore an ideal target for treatment. To test whether integrin α6β4 contributes to this regulation through DNA methylation pancreatic cancer cells expressing low levels of α6β4 were treated with DNA methyltransferase inhibitor 5-aza-2′deoxycitidine. Using Q-PCR, our results show that inhibition of DNA methyltransferase increases amphiregulin and epiregulin expression at the mRNA level. In contrast, when cells with high levels of integrin α6β4 were treated with the hypermethylating agent, S-adenosylmethionine, it leads to a decrease in amphiregulin and epiregulin expression. This implicates α6β4 as a regulator of this process allowing us insight into how this pathway might be regulated. Using ELISA, we also provide evidence that integrin α6β4 promotes increased autocrine secretion of amphiregulin after promoter demethylation. This is of particular interest to our lab because autocrine secretion of amphiregulin and epiregulin make it possible for cancer cells to both produce and respond to their own growth factors, promoting cellular invasion and metastasis. This study indicates that overexpression of integrin α6β4 in pancreatic cancer is associated with the hypomethylation of amphiregulin and epiregulin promoters, which may play an important role in the development of a malignant phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3134. doi:1538-7445.AM2012-3134

UCP4 overexpression improves fatty acid oxidation and insulin sensitivity in L6 myocytes

Obesity, which is caused by energy uptake being greater than energy expenditure, is widely prevalent today. Currently, only a limited number of efficient interventional strategies are available for the prevention of obesity. Previous studies have shown that UCP4 transcription occurs at a considerable level in mouse skeletal muscle; however, the exact functions of UCP4 remain unclear. In this study, we investigated the effect of UCP4 on mitochondrial function and insulin sensitivity in mature L6 myocytes. UCP4 overexpression in L6 myocytes induced increased mitochondrial carnitine palmitoyltransferase 1A (CPT1A) and decreased citrate synthase (CS) mRNA in the basal condition (i.e., in the absence of insulin). UCP4 overexpression significantly improved insulin sensitivity, increased tyrosine phosphorylation of IRS-1 in the presence of insulin, and significantly reduced intracellular triglyceride (TG). Additionally, intracellular ATP content and mitochondrial membrane potential were downregulated. We also observed that intracellular ROS, mitochondrial morphology, and mitochondrial mtDNA copy number were maintained upon UCP4 expression, with no change in mitochondrial fusion and fission. In summary, our findings provide evidence to show that UCP4 overexpression reduced the insulin sensitivity and mitochondrial fatty acid oxidation of L6 myocytes. These findings support the notion that UCPs are ideal targets for treatment of insulin resistance.

Telomeres and prognosis in patients with chronic lymphocytic leukaemia

In the present study, telomere length, telomerase activity, the mutation load of immunoglobulin variable heavy chain (IGHV) genes, and established prognostic factors were investigated in 78 patients with chronic lymphocytic leukaemia (CLL) to determine the impact of telomere biology on the pathogenesis of CLL. Telomere length was measured by an automated multi-colour flow-FISH, and an age-independent delta telomere length (ΔTL) was calculated. CLL with unmutated IGHV genes was associated with shorter telomeres (p=0.002). Furthermore, we observed a linear correlation between the frequency of IGHV gene mutations and elongation of telomeres (r=0.509, p<0.001). With respect to prognosis, a threshold ΔTL of -4.2kb was the best predictor for progression-free and overall survival. ΔTL was not significantly altered over time or with therapy. The correlation between the mutational load in IGHV genes and the ΔTL in CLL might reflect the initial telomere length of the putative cell of origin (pre- versus post-germinal center B cells). In conclusion, the ΔTL is a reliable prognostic marker for patients with CLL. Short telomeres and high telomerase activity as occurs in some patients with CLL with a worse prognosis might be an ideal target for treatment with telomerase inhibitors.

Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration

Angiogenesis has a causal role in many diseases, including neovascular age-related macular degeneration (AMD). Identification of key regulators of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules, has facilitated the development of novel therapeutic agents that target the underlying pathological angiogenic process. Among these, VEGF serves as a "master switch" for many ocular neovascular conditions through its promotion of endothelial cell proliferation and survival, vascular permeability and ocular inflammation.Two anti-VEGF agents are now clinically available: bevacizumab, an antibody for metastatic colorectal cancer, and pegaptanib sodium, an aptamer for neovascular AMD. Unlike bevacizumab, which binds all VEGF isoforms, pegaptanib targets only VEGF 165, the isoform responsible for pathological ocular neovascularization and thus an ideal target for treatment of AMD. Although other therapies targeting angiogenesis in AMD are in clinical development, to date, pegaptanib is the only therapy approved by the Food and Drug Administration of the United States for the treatment of all neovascular AMD and represents a valuable addition to the hitherto limited options available for patients.

COMPOUNDS FIGHT ARTERY NARROWING

CIRCULAR COMPOUNDS FROM a common soil fungus show promise in treating Researchers in Japan discovered that beauveriolides I and III, 13-membered cyclic depsipeptides made of three amino acids and a fatty acid, inhibit the buildup of macrophage lipids in a mouse with atherosclerotic arteries { Proc. Natl. Acad. Sci. USA , 101 , 737 (2004)}. Lipid buildup is one of the essential steps of plaque formation, which leads to artery narrowing. The scientists further elucidated the fungal compounds' specific target: the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Coauthor Hiroshi Tomoda, a professor of lipid biochemistry at Kitasato University, notes that plays multiple roles in our body: cholesterol absorption from the intestine, lipoprotein production in the liver, and atherosclerogenesis in the artery. Therefore, researchers believe that ACAT is an ideal target for treatment of atherosclerosis. Other ACAT inhibitors have already been identified. The major significance of the new ...