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Biodistribution of VEGF-4-1BB conjugate. Survival assay in MCA induced fibrosarcoma model. Cytokine levels in treated animals. Tumor volume studies with combinatorial therapy in Balb/c model. Histology and morphology for toxicity profiles.

Purpose:Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.Patients and Methods:Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.Results:In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.Conclusions:Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868

Figure S1: Alisertib treatment did not result in a consistent cytokine response. Figure S2: Alisertib did not have a consistent effect on TGF-b levels. Figure S3: Alisertib induced GATA1 expression in the SET2 megakaryocytic cell line. Figure S4: AURKA inhibition induces megakaryocytic gene expression. Figure S5: Alisertib increases GATA1 expression in the bone marrow of patients on therapy. Table S1: Correlation of Genotype and prior JAK inhibitor therapy with response and adverse events Table S2: Summary of Treatment Related Adverse Events Table S3: Association between GATA1 staining, degree of fibrosis and clinical response

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310–21. ©2017 AACR.

Sulphadiazine and their copper metal complexes are dexterous ligands, which are condensation products of primary amines with carbonyl compounds gaining importance day by day in the present scenario. Spectral characterization and examination of the potential antimicrobial and antioxidant activity of the synthesized complex were performed. The imine Cu(II) complex is characterized by FTIR and UV/Vis spectroscopy. The Stoichiometric M:L ratio was determined by Joe and Jones method. These compounds and their copper metal complex are very important in various biological systems and their medicinal and pharmaceutical fields. Schiff foundations show beneficial natural functions such as anti-inflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic, and antiglycation. The present review summarizes information on the diverse biological activities and also highlights the recently synthesized numerous Schiff bases and their metal complex as potential bioactive core.

There is an ever-rising prevalence of myopia in our population. Many individuals are being diagnosed with myopia; however, the treatment for myopia is relatively the same. Evidence has shown that there is the involvement of extraocular muscles as well in the development of myopia. These muscles can be trained and may prove useful in improving myopia. Thus it is important to study the effects of ocular exercises on myopia. The objective of this study was to find out the effect of ocular muscle exercises on the degree of myopia. There was a total of 46 subjects who were willing participants of this study. Pre-intervention and post-intervention visual acuity was analyzed. The experimental group received ocular exercises, and the control group was advised to follow a routine for six weeks. There was no significant effect of ocular muscle exercises on the degree of myopia post-intervention (p = 0.3275). Based on the result of the study, it can be said that the ocular exercise does not affect the improvement in the visual acuity in an individual. Similarly, the ocular muscle exercises were not effective in improving the degree of myopia.

Purpose: Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis. Patients and Methods: Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis. Results: In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients. Conclusions: Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis. See related commentary by Piszczatowski and Steidl, p. 4868

Background: The dependence of today’s younger generation on technology is increasing and the work hours spent by professionals in front of computer screens are also increasing. These are the leading causes of myopia. Task related postural adaptation may also cause myopia. However, very few if any people suffering from myopia are being referred to a physiotherapist. There is positive effect of ocular muscle exercises on increasing visual acuity and decreasing stress on the ocular muscles. Objective: The objective of this study was to find out the effect of ocular muscle exercises on myopic individuals with forward head posture. Method: There were total 46 subjects who were willing participants of this study. They were divided in two groups one excremental who received exercises while other was control. Pre intervention and post intervention postural assessment were taken and analysed. Result: There was a significant effect of the ocular exercises on craniovertebral angle of these myopic individuals compared control group (p = 0.0219). Its effect on forward shoulder angle was not quite significant (p = 0.0619). Conclusion: Ocular exercises are not quite effective in improving forward head posture.

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310–21. ©2017 AACR.

Pheochromocytomas (PCCs) are rare catecholamine-secreting tumors arising from adrenomedullary chromaffin cells, usually causing hypertension, palpitation, and headache. It is usually investigated as a secondary cause of hypertension. However, rarely it can present in hypotension. In “PCC crisis,” the patient presents with hypotension, multiple organ dysfunction, leaving the physician with diagnostic difficulties. In this case, we present an adolescent male presented with hypotensive cardiogenic shock, and multiple organ dysfunction on admission, which during investigation turned out to be bilateral PCC.

T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors.

Background: The selective AURKA inhibitor alisertib (MLN8237) exhibits disease modifying activity in murine models of myelofibrosis by eradicating atypical megakaryocytes resulting in reduction of marrow fibrosis (Nat Med 2015). Here, we present long term follow-up results from the investigator initiated pilot study of alisertib in patients with myelofibrosis (clinical trials.gov Identifier NCT 02530619). Methods: 24 patients with DIPSS intermediate 1, intermediate-2, or high risk myelofibrosis who were in need of therapy, refractory/intolerant or unlikely to respond to JAK inhibitors with neutrophil count ≥ 1 x109/L, and platelet count ≥ 50 x109/L, received alisertib (provided by Millennium Pharmaceuticals Inc) at a dose of 50 mg twice daily for one week every 21 days. Toxicity assessment was performed by the standard common terminology criteria (Version 4.0). Response was assessed by the international working group for myelofibrosis research and treatment (IWGMRT) criteria. Correlative studies included assessments of JAK2V617F, CALR, and MPL mutant allele burden, degree of fibrosis and GATA1 expression in bone marrow samples obtained pre and post therapy. Results: We enrolled 17 patients with primary myelofibrosis, 4 with post essential thrombocythemia myelofibrosis and 3 with post polycythemia vera myelofibrosis. Median age was 72 years with 66% males. 79% of patients were DIPSS intermediate risk, and the remainder were high risk with 15 patients (62.5%) having received prior JAK inhibitor therapy. Driver mutational status was as follows; 58% JAK2V617F, 29% CALR, and 13% MPL mutated. At study entry, 54% of patients demonstrated palpable splenomegaly ≥ 5 cm below the left costal margin, 54% were transfusion dependent with all patients experiencing constitutional symptoms. At the time of data cut-off, patients received a median of 7.5 cycles (range; 1-29 cycles) of therapy. The 7 patients presently on study have received a median of 23 cycles (range; 8-29 cycles). Reasons for treatment discontinuation included progressive disease/lack of response in 11 (65%) patients, toxicity in 4 (24%) patients and refusal of further therapy in 2 (11%) patients.Safety and Efficacy assessments The most common treatment-emergent grade 3/4 adverse events included neutropenia (42%), thrombocytopenia (29%) and anemia (21%), with 4% each experiencing neutropenic fever, diarrhea, vertigo, elevated creatinine and elevated alanine aminotransferase. 22 patients were considered for response evaluation with 4 of 14 patients (29%) with palpable splenomegaly ≥ 5 cm achieving a spleen response, 1 of 13 patients (8%) becoming transfusion independent, and 5 of 22 patients (23%) experiencing symptom response with ≥ 50% reduction in the MPN-SAF total symptom score. However, when response assessment was restricted to 13 patients who had received a minimum of 5 cycles of therapy, spleen responses were observed in 4 of 7 (57%) patients, 1 of 5 (20%) achieved transfusion independence and 5 of 13 (38%) achieved symptom response. All patients presenting with leukocytosis (n=4) and thrombocytosis (n=2) had resolution with therapy. Of the 7 patients presently on study, four patients continue to demonstrate symptom response, two patients with both spleen and symptom response, and another patient with sustained anemia response. Correlative assessments We compared the intensity of staining of GATA1, a factor that is required for maturation, in sequential bone marrow biopsies from six patients at baseline and after a minimum of five cycles and observed a striking increase in the numbers of GATA1-positive megakaryocytes in five of six cases (Figure 1a). In addition, we observed a one grade reduction in marrow fibrosis in 4 of 6 paired samples (Figure 1b). This reduction in fibrosis was accompanied by sustained responses to the drug. Finally, we compared JAK2, MPL or CALR mutant allele burden in eight paired baseline and cycle 5 or 6 samples and observed decreases in 4 of 8 patients (Figure 1c). Conclusions: Alisertib is safe and well tolerated in patients with myelofibrosis with prolonged administration up to 1.7 years. In addition to providing clinical benefit, alisertib restored normal morphology and GATA1 expression in atypical megakaryocytes and reduced marrow fibrosis and mutant allele burdens. These findings demonstrate that AURKA inhibition should be further explored as a therapeutic option in myelofibrosis. Figure 1. Figure 1. Disclosures Swords: AbbVie: Employment. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Frankfurt:Celgene, Jazz, Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees. Altman:Cyclacel: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Genetech: Other: Payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work. Rampal:Celgene: Honoraria; Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria. Giles:Actuate Therapeutics Inc: Employment, Equity Ownership. Crispino:Forma Therapeutics: Research Funding; Scholar Rock: Research Funding.

Radiotherapy (RT)-potentiated immunomodulation is an emerging field in solid tumor malignancies. RT induces peripheral antitumor immunity that can lead to the reduction of distant, non-irradiated tumor lesions (abscopal response). This has provided rationale for current early phase trials combining existing checkpoint blockade and co-stimulatory mAbs with stereotactic RT. Objective responses remain suboptimal with checkpoint blockade monotherapy, and dose limiting toxicity is widely observed with these modalities. We hypothesize that targeting immunotherapy to the tumor using oligonucleotide aptamers that bind to RT induced tumor stress products will significantly enhance the therapeutic index. We used the aptamer platform to generate a bi-specific construct containing a costimulatory aptamer ligand specific to murine 4-1BB which was conjugated to an aptamer specific to products secreted into the tumor stroma (VEGF or osteopontin). Tumor targeting, local control, abscopal responses and toxicity were compared to unconjugated 4-1BB-VEGF constructs, or mAB based therapies, when used in combination with RT in murine subcutaneous and autochthonous MCA tumor models. RT induced VEGF upregulation was demonstrated in null/low VEGF secreting tumors that led to preferential accumulation of VEGF-41BB aptamers in the irradiated tumor.12Gy x1 elicited optimal tumor targeting of bi-specific VEGF-4-1BB conjugate. Significant anti-tumor immune responses were observed in s.c. murine tumor models. This conjugate showed dramatic reduction in systemic toxicity compared to the equivalent gold standard 4-1BB mAb. RT-VEGF-4-1BB treatment significantly improved local control, overall survival and induced potent abscopal responses compared to unconjugated and non-irradiated controls in the Balb/c 4T1 and MCA murine tumor models. Furthermore, RT-VEGF-4-1BB treatment showed similar anti-tumor effects as CTLA-4 mAB with significantly less systemic toxicity. This approach increased intra-tumoral CD4+ and CD8+ T cells, the CD8+ to Treg ratio, and induced significantly more tumor cell death. In conclusion, this strategy has been shown to induce potent anti-tumor immune responses in relevant murine tumor models and significantly improves the therapeutic index over non-targeted mABs. Furthermore, radiotherapy can expand the scope of tumor targeted immune modulation to virtually all solid malignancies and induce potent abscopal responses. These results provide the rationale for developing clinical grade bispecific aptamers for future testing. Citation Format: Brett Schrand, Bhavna Verma, Agata Levay, Shradha Patel, Iris Castro, Ana Paula Benaduce, Randall Brenneman, Oliver Umland, Hideo Yagita, Eli Gilboa, Adrian Ishkanian. Radiation-induced vegf-targeted 4-1bb costimulation enhances immune control of tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1700. doi:10.1158/1538-7445.AM2017-1700