MULTILEVEL DEREGULATION OF SURVIVAL MECHANISMS IN NPM-ALK+ T-CELL LYMPHOMA

The anaplastic lymphoma kinase (ALK) is a single chain transmembrane receptor tyrosine kinase that belongs to the insulin receptor superfamily. Other members of this superfamily include the insulin receptor (IR), type I insulin-like growth factor receptor (IGF-IR), and the leukocyte tyrosine kinase. The common structural finding among these tyrosine kinases is the YXXXYY motif present within their respective tyrosine kinase domains. Binding of its ligands causes ALK receptor homodimerization and protein kinase activation. ALK has been previously shown to play a significant role during early developmental stages. In human embryos, the expression of ALK is mainly seen in the nervous system but it decreases at birth. A variety of structural rearrangements have been identified in the ALK gene, such as mutations, overexpression, and translocations, often leading to the production of oncogenic proteins found in several different types of human cancers, such as nucleophosmin-anaplastic lymphoma kinase-expressing anaplastic large-cell lymphoma (NPM-ALK+ ALCL). The oncogenic potential of NPM-ALK has been demonstrated by several studies using in vitro assays as well as transgenic mouse models. NPM-ALK+ ALCL is an aggressive subset of T-cell lymphoma that predominantly occurs in children and young adults. It comprises approximately 85% of ALK+ ALCL cases and is characterized by the translocation t(2;5)(p23;q35) that leads to the fusion between the NPM gene on chromosome 5q35 and the ALK gene on chromosome 2p23 generating the NPM-ALK oncogene, which encodes the expression of NPM-ALK chimeric tyrosine kinase. NPM-ALK induces lymphomagenic effects through the formation of the constitutively activated NPM-ALK/NPM-ALK homodimers, which phosphorylate/activate downstream survival-promoting proteins including JAK/STAT, PI3K/AKT, and MAP kinase. NPM-ALK resides in the cytoplasm; nonetheless, it is also capable of forming the wild type NPM/NPM-ALK heterodimers that translocate to the nucleus through the nuclear localization signal site present in wild type NPM. IGF-IR is a homodimeric protein that is composed of two extracellular α and two transmembranous β subunits connected by disulfide bonds. Similar to ALK, its expression plays an important role during early developmental stages. Mouse models have confirmed the importance of IGF-IR in prenatal and postnatal growth through its interactions with the growth hormone. The result of activation of IGF-IR during these stages is survival and proliferation of cells resulting in developmental growth of tissues such as skeletal and cardiac muscles. It also plays a critical role during growth of the mammary gland during pregnancy and lactation. It has been previously shown that Igf1r null mice develop generalized organ hypoplasia, such as developmental delays in bone ossification, abnormalities in the central nervous system, and they prematurely die because of underdevelopment of their lungs that leads to respiratory failure. Recently, it has been shown that IGF-IR overexpression significantly contributes to the establishment and progression of different types of cancer and to the emergence of therapeutic resistance. These effects have been extensively investigated in solid tumors including breast, prostate, lung, ovary, skin, and soft tissue cancers. We have recently demonstrated that, compared with normal human T lymphocytes and reactive lymphoid tissues, the expression and activation of IGF-IR are remarkably upregulated in NPM-ALK+ ALCL. We also demonstrated that IGF-IR physically associates and directly interacts with NPM-ALK. Nonetheless, the exact mechanisms for the up-regulation of IGF-IR and NPM-ALK in this lymphoma are not fully characterized. We hypothesized that multilevel deregulation of survival mechanisms contributes to aberrant NPM-ALK and IGF-IR expression, which supports the survival and progression of NPM-ALK+ ALCL

Using data science as a community advocacy tool to promote equity in urban renewal programs: An analysis of Atlanta's Anti-Displacement Tax Fund

Cities across the United States are undergoing great transformation and urban growth. Data and data analysis has become an essential element of urban planning as cities use data to plan land use and development. One great challenge is to use the tools of data science to promote equity along with growth. The city of Atlanta is an example site of large-scale urban renewal that aims to engage in development without displacement. On the Westside of downtown Atlanta, the construction of the new Mercedes-Benz Stadium and the conversion of an underutilized rail-line into a multi-use trail may result in increased property values. In response to community residents' concerns and a commitment to development without displacement, the city and philanthropic partners announced an Anti-Displacement Tax Fund to subsidize future property tax increases of owner occupants for the next twenty years. To achieve greater transparency, accountability, and impact, residents expressed a desire for a tool that would help them determine eligibility and quantify this commitment. In support of this goal, we use machine learning techniques to analyze historical tax assessment and predict future tax assessments. We then apply eligibility estimates to our predictions to estimate the total cost for the first seven years of the program. These forecasts are also incorporated into an interactive tool for community residents to determine their eligibility for the fund and the expected increase in their home value over the next seven years.Comment: Presented at the Data For Good Exchange 201

Enhanced AODV Routing Protocol Using Leader Election Algorithm

Failure of communication link in mobile ADHOC network is major issue. For the failure of link the performance of network is degraded. Due to mobility of mobile node brake the communication link and path of routing is failed. For the repairing of routing node used various algorithm such as leader election, distributed and selection algorithm. The failure of link decease the performance of routing protocol in mobile ad-hoc network, for the improvement of quality of service in mobile ad-hoc network various authors proposed a different model and method for prediction of link. The prediction of link decreases the failure rate of mobile node during communication. The leader election algorithm plays a major role in link failure prediction algorithm the process of link failure prediction implied in form of distributed node distribution. Proposed a new link stability prediction method based on current link-related or user-related information in shadowed environments. The modified protocol acquired the process of thresholds priority Oder on the basic of neighbor’s node. The selection of neighbor node deepens on the mode operation in three sections. According to order of state create cluster of priority of group. After creation of group calculate average threshold value and compare each group value with minimum threshold value and pass the control message for communication. Through this process mode of activation state of node is minimized the time of route establishment and maintenance. The selection of proper node in minimum time and other node in sleep mode the consumption of power is reduces. We modified SBRP protocol for selection of node during on demand request node according to sleep and activation mode of communication. Each node locally assigned priority value of node. For the evaluation of performance used network simulator NS-2.35. And simulate two protocol one is AODV-LE protocol, these protocol patch are available for the simulation purpose. And another protocol is AODV-LE-ME. AODV-LE-ME protocol is modified protocol of leader election protocol for the selection of mobile node during the communication. DOI: 10.17762/ijritcc2321-8169.15016

Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

PurposeWe hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.Experimental designPatients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.ResultsNinety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).ConclusionCombination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved

Johansen model for photovoltaic a very short term prediction to electrical power grids in the Island of Mauritius

Sudden variability in solar photovoltaic (PV) power output to electrical grid can not only cause grid instability but can also affect power and frequency quality. Therefore, to study the balance of electrical grid or micro-grid power generated by PV systems in an upstream direction, predicting models can help. The power output conversion is directly proportional to the solar irradiance. Unlike time horizons predictions, many technics of irradiance forecasting have been proposed, long, medium and short term forecasting. For the Island of Mauritius in the Indian Ocean, and regards to key policy decisions, the government has outlined its intention to promote the PV technologies through the local electricity supplier but oversee the technical requirements of PV power output predicts for 1 hour to 15-minutes ahead. So, this paper is illustrating results of the Johansen vector error correction model (VECM) cointegration approach, from the author original and previous studies, but for a very short term prediction of 15-minutes to PV power output in Mauritius. The novelty of this study, is the long run equilibrium relationship of the Johansen model, that was initially determined in previous research works and from dataset in Reunion Island, is then applied to the PV plant in the Island of Mauritius. The proposed prediction model is trained for an hourly and 15-minutes period from year 2019 to year 2022 for a random month and a random day. The experimental results show that the performance metric R2 values are more than 93% signifying that Johansen model is positively and strongly correlated to onsite measurements. This proposed model is a powerful predicting tool and more accuracy should be attained when associated to a machine learning method that can learn from datasets

EXPLORING FISH MISCELLANY FROM BIODIVERSITY HOTSPOT REGION OF NORTHEAST INDIA THROUGH CHROMOSOME PROFILING

Sjeveroistočne države Indije obiluju ekstenzivnim ekoklimatskim uvjetima te sadrže veliki dio indijske endemske flore i faune. Ova regija obiluje ribljom raznolikošću s mnoštvom vrsta akvarijskih riba, uključujući zebricu. Među potencijalnim ukrasnim ribama, Ctenops nobilis označena je kao gotovo ugrožena, a Danio dangila uključena je na popis najmanje zabrinutosti IUCN-a. Ovdje je poduzeto citogenetsko profiliranje kako bi se osigurali komplementarni podaci za preciznu identifikaciju vrsta i proučavanje genetskog nasljeđa, organizacije genoma i evolucije vrste. Citogenetskim analizama utvrđen je diploidni broj kromosoma 44 i 50 s formulom kariotipa 8m+20sm+10st+6t (FN=72) odnosno 20m+24sm+6st (FN=94) u C. nobilis i D. dangila. Bojanje nukleolarnih regija otkrilo je prisutnost Ag-NORs, CMA3 mjesta i signala gena 18S rDNA na jednom paru subtelocentričnog kromosoma i jednom paru submetacentričnog kromosoma u C. nobilis i D. dangila. Ovi biomarkeri važan su izvor za molekularnu taksonomiju, evolucijske/filogenetske studije i genetiku očuvanja C. nobilis i D. dangila.North Eastern states of India are blessed with extensive ecoclimatic conditions and much of India’s endemic flora and fauna. This region is rich in fish diversity with plenty of species of ornamental importance, including model species zebrafish. Among the potential ornamental fishes, Ctenops nobilis is designated as Near Threatened and Danio dangila is included in the Least Concern list by IUCN. Cytogenetic profiling was undertaken here to provide complementary data for precise species identification and to study genetic inheritance, genome organization and evolution of the species. The cytogenetic analyses revealed diploid chromosome numbers 44 and 50 with karyotype formula 8m+20sm+10st+6t (FN=72) and 20m+24sm+6st (FN=94), respectively, in C. nobilis and D. dangila. The staining of nucleolar organizer regions revealed the presence of Ag-NORs, CMA3 sites and 18S rDNA probe signals on one pair sub-telocentric chromosome and one pair sub-metacentric chromosome in C. nobilis and D. dangila, respectively. These biomarkers are an important resource for molecular taxonomy, evolutionary/phylogenetic studies and conservation genetics of C. nobilis and D. dangila

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Minimum energy conformations of DNA dimeric subunits: Potential energy calculations for dGpdC, dApdA, dCpdC, dGpdG, and dTpdT

Minimum energy conformations have been calculated for the deoxydinucleoside phosphates dGpdC, dApdA, dCpdC, dGpdG, and dTpdT. In these potential energy calculations the eight diheldral angles and the sugar pucker were flexible parameters. A substantial survey of conformation space was made in which all staggred combination of the dihedral angles ω′,ω, and ψ, in conjunction with C(2′)-endo pucker, were used as starting conformers for the energy minimization. The most important conformations in the C(3′)-endo-puckering domain have ψ = g+; ω′,ω = g−,g−(A-form),g+, g+, and g−,t. With C(2′)-endo-type pucker the most important conformations have ψ = g+; ω′,ω =g-,g-(B-form) and g+,t; and ψ =t; ω′,ω =g-,t(Watson-Crick from) and t,g+ (skewed). Stacked bases are a persistent feature of the low-energy conformations, the g+ conformer being an exception. Freeing the suger pucker allowed this conformation to become low energy, with C(3′)-exo pucker. It also caused other low-energy forms, such and the Waston-Crick conformation, to become more favourable. Conformation flexibility in the sugar pucker and in ψ, as well as the ω′,ω angle pair, is indicated for the dimeric subunits of DNA