Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma.

Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood-brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 µM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers.

Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma.

Adult T-cell leukemia and lymphoma (ATLL) is an intractable T-cell neoplasia caused by a retrovirus, namely human T-cell leukemia virus type 1 (HTLV-1). Patients suffering from ATLL present a poor prognosis and have a dearth of treatment options. In contrast to the sporadic expression of viral transactivator protein Tax present at the 5' promoter region long terminal repeats (LTR), HTLV-1 bZIP gene (HBZ) is encoded by 3'LTR (the antisense promoter) and maintains its constant expression in ATLL cells and patients. The antisense promoter is associated with selective retroviral gene expression and has been an understudied phenomenon. Herein, we delineate the activity of transcription factor MEF (myocyte enhancer factor)-2 family members, which were found to be enriched at the 3'LTR and play an important role in the pathogenesis of ATLL. Of the four MEF isoforms (A to D), MEF-2A and 2C were highly overexpressed in a wide array of ATLL cell lines and in acute ATLL patients. The activity of MEF-2 isoforms were determined by knockdown experiments that led to decreased cell proliferation and regulated cell cycle progression. High enrichment of MEF-2C was observed at the 3'LTR along with cofactors Menin and JunD resulting in binding of MEF-2C to HBZ at this region. Chemical inhibition of MEF-2 proteins resulted in the cytotoxicity of ATLL cells in vitro and reduction of proviral load in a humanized mouse model. Taken together, this study provides a novel mechanism of 3'LTR regulation and establishes MEF-2 signaling a potential target for therapeutic intervention for ATLL.

Development of a Wireless Telemetry Sensor Device to Measure Load and Deformation in Orthopaedic Applications.

Due to sensor size and supporting circuitry, in-vivo load and deformation measurements are currently restricted to applications within larger orthopaedic implants. The objective of this study is to repurpose a commercially available low-power, miniature, wireless, telemetric, tire-pressure sensor (FXTH87) to measure load and deformation for future use in orthopaedic and biomedical applications. The capacitive transducer membrane was modified, and compressive deformation was applied to the transducer to determine the sensor signal value and the internal resistive force. The sensor package was embedded within a deformable enclosure to illustrate potential applications of the sensor for monitoring load. To reach the maximum output signal value, sensors required compressive deformation of 350 ± 24 µm. The output signal value of the sensor was an effective predictor of the applied load on a calibrated plastic strain member, over a range of 35 N. The FXTH87 sensor can effectively sense and transmit load-induced deformations. The sensor does not have a limit on loads it can measure, as long as deformation resulting from the applied load does not exceed 350 µm. The proposed device presents a sensitive and precise means to monitor deformation and load within small-scale, deformable enclosures.

Human T-cell Leukemia Virus Type 1 and Strongyloides stercoralis: Partners in Pathogenesis.

Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with Strongyloides stercoralis, which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions citing high prevalence of S. stercoralis infection, making these communities optimal for elucidating the pathogenesis of co-infection and its clinical significance. HTLV-1 co-infection with S. stercoralis has been observed for decades in a number of published patient cases and case series; however, the implications of this co-infection remain elusive. Thus far, data suggest that S. stercoralis increases proviral load in patients co-infected with HTLV-1 compared to HTLV-1 infection alone. Furthermore, co-infection with HTLV-1 has been associated with shifting the immune response from Th2 to Th1, affecting the ability of the immune system to address the helminth infection. Thus, despite this well-known association, further research is required to fully elucidate the impact of each pathogen on disease manifestations in co-infected patients. This review provides an analytical view of studies that have evaluated the variation within HTLV-1 patients in susceptibility to S. stercoralis infection, as well as the effects of strongyloidiasis on HTLV-1 pathogenesis. Further, it provides a compilation of available clinical reports on the epidemiology and pathology of HTLV-1 with parasitic co-infection as well as data from mechanistic studies suggesting possible immunopathogenic mechanisms. Furthermore, specific areas of potential future research have been highlighted to facilitate advancing understanding of the complex interactions between these two pathogens.

Maf1-dependent transcriptional regulation of tRNAs prevents genomic instability and is associated with extended lifespan.

Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1's function in tRNA repression is inhibited by mTOR-dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1-dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes.

Endoscopic treatment of chronic radiation proctopathy.

PURPOSE OF REVIEW: Chronic radiation proctopathy is a complication of pelvic radiation therapy. The acute phase of radiation injury to the rectum occurs during or up to 3 months following radiation. Acute radiation injury can continue into a chronic phase or chronic radiation proctopathy may develop after a latent period of several months or years. Symptoms associated with the condition include diarrhea, rectal pain, bleeding, tenesmus, and stricture formation. Of the various symptoms, only bleeding from radiation-induced telangiectasias is amenable to endoscopic therapy. This paper summarizes the findings of experts in the field on endoscopic treatment of bleeding from chronic radiation proctopathy. RECENT FINDINGS: Medical management is generally ineffective in controlling bleeding from chronic radiation proctopathy. Surgical intervention has a high incidence of morbidity. Promising advances have been made in endoscopic therapy, including formalin, neodymium/yttrium aluminum garnet, argon and potassium titanyl phosphate laser treatments, as well as argon plasma coagulation. Argon plasma coagulation presents an effective, efficient, inexpensive and reasonably safe noncontact method for destruction of radiation telangiectasias. SUMMARY: Based on currently available data and trends, argon plasma coagulation is the favored treatment for bleeding from chronic radiation proctopathy.