Hit Score Research Articles

Safety screening in early drug discovery: An optimized assay panel

BackgroundSeveral factors contribute to the development failure of novel pharmaceuticals, one of the most important being adverse effects in pre-clinical and clinical studies. Early identification of off-target compound activity can reduce safety-related attrition in development. In vitro profiling of drug candidates against a broad range of targets is an important part of the compound selection process. Many compounds are synthesized during early drug discovery, making it necessary to assess poly-pharmacology at a limited number of targets. This paper describes how a rational, statistical-ranking approach was used to generate a cost-effective, optimized panel of assays that allows selectivity focused structure-activity relationships to be explored for many molecules.This panel of 50 targets has been used to routinely screen Roche small molecules generated across a diverse range of therapeutic targets. Target hit rates from the Bioprint® database and internal Roche compounds are discussed. We further describe an example of how this panel was used within an anti-infective project to reduce in vivo testing. MethodTo select the optimized panel of targets, IC50 values of compounds in the BioPrint® database were used to identify assay “hits” i.e. IC50 ≤ 1 μM in 123 different in vitro pharmacological assays. If groups of compounds hit the same targets, the target with the higher hit rate was selected, while others were considered redundant. Using a step-wise analysis, an assay panel was identified to maximize diversity and minimize redundancy. Over a five-year period, this panel of 50 off-targets was used to screen ≈1200 compounds synthesized for Roche drug discovery programs. Compounds were initially tested at 10 μM and hit rates generated are reported. Within one project, the number of hits was used to refine the choice of compounds being assessed in vivo. Results95% of compounds from the BioPrint® panel were identified within the top 47-ranked assays. Based on this analytical approach and the addition of three targets with established safety concerns, a Roche panel was created for external screening. hERG is screened internally and not included in this analysis. Screening at 10 μM in the Roche panel identified that adenosine A3 and 5HT2B receptors had the highest hit rates (~30%), with 50% of the targets having a hit rate of ≤4%. An anti-infective program identified that a high number of hits in the Roche panel was associated with mortality in 19 mouse tolerability studies. To reduce the severity and number of such studies, future compound selections integrated the panel hit score into the selection process for in vivo studies. It was identified that compounds which hit less targets in the panel and had free plasma exposures of ~2 μM were generally better tolerated. DiscussionThis paper describes how an optimized panel of 50 assays was selected on the basis of hit similarity at 123 targets. This reduced panel, provides a cost-effective screening panel for assessing compound promiscuity, whilst also including many safety-relevant targets. Frequent use of the panel in early drug discovery has provided promiscuity and safety-relevant information to inform pre-clinical drug development at Roche.

Cloud identification and classification from high spectral resolution data in the far infrared and mid-infrared

Abstract. A new cloud identification and classification algorithm named CIC is presented. CIC is a machine learning algorithm, based on principal component analysis, able to perform a cloud detection and scene classification using a univariate distribution of a similarity index that defines the level of closeness between the analysed spectra and the elements of each training dataset. CIC is tested on a widespread synthetic dataset of high spectral resolution radiances in the far- and mid-infrared part of the spectrum, simulating measurements from the Fast Track 9 mission FORUM (Far-Infrared Outgoing Radiation Understanding and Monitoring), competing for the ESA Earth Explorer programme, which is currently (2018 and 2019) undergoing industrial and scientific Phase A studies. Simulated spectra are representatives of many diverse climatic areas, ranging from the tropical to polar regions. Application of the algorithm to the synthetic dataset provides high scores for clear or cloud identification, especially when optimisation processes are performed. One of the main results consists of pointing out the high information content of spectral radiance in the far-infrared region of the electromagnetic spectrum to identify cloudy scenes, specifically thin cirrus clouds. In particular, it is shown that hit scores for clear and cloudy spectra increase from about 70 % to 90 % when far-infrared channels are accounted for in the classification of the synthetic dataset for tropical regions.

Extracorporeal shock wave therapy has an excellent therapeutic effect on plantar fasciitis

Objective To explore the long-term effectiveness of using extracorporeal shock waves in the treatment of plantar fasciitis. Methods Extracorporeal shock wave therapy was applied to 23 plantar fasciitis sufferers once a week for three weeks. MRI examinations were performed before and 4 hours after the first treatment. Before the treatment and one month after it was complete, all of the patients rated their pain using a visual analogue scale (VAS), and their infirmity was quantified using a heel tenderness index (HTI) and the ankle-hind foot scale of the American Orthopaedic Foot and Ankle Society (AOFAS). The longest walking time was also recorded. Paired t-tests compared the T2 values of the fascia, muscles and fat pads, the longest walking time and the VAS scores before and after the treatment. Pearson correlation coefficients were evaluated to test the significance of any correlation between the T2 changes and the changes in the VAS scores. Results After the shock wave therapy, the average VAS, HIT and AOFAS scores had significantly decreased, while the longest walking time had increased significantly. The magnetic resonance imaging showed increased edema in the fascia and their surrounding soft tissues. And the extent and degree of the T2 weighted high signal increased four hours after the treatment. The changes in the T2 values correlated positively and significantly with the changes in the VAS scores. Conclusion Extracorporeal shock waves have an excellent therapeutic effect on plantar fasciitis. They can significantly relieve heel pain and improve foot movement. Key words: Plantar fasciitis; Extracorporeal shock wave therapy; Magnetic resonance imaging; Therapeutic effectiveness

A NEW HIGH-RESOLUTION INVASION TEST (HIT) CAN PREDICT MALIGNANT TRANSFORMATION IN ORAL EPITHELIAL DYSPLASIAS

Rationale Detecting the earliest signs of invasion and predicting transformation in oral potentially malignant lesions (OPMLs) can facilitate earlier treatment of oral squamous cell carcinoma (OSCC) and decrease morbidity and mortality. Here we described a new test to diagnose early invasion and predict malignant transformation in OPML. Methods Fluorescent immunohistochemist and multichannel colocalization were used to identify invadopodia markers FISH, cortactin and MMP14 in OSCC and OPML. The presence of invadopodia markers was calculated using 3-channel colocalization analysis based on a custom algorithm developed using Volocity Software. The threshold for colocalization was determined by linear least-square fit of the channel intensities and the product of the difference of the means was (PDM) was used to compare the area of colocalization (HIT score). This algorithm was applied to 80 cases (10 cases of non-dysplastic hyperkeratosis, 22 cases of epithelial dysplasias (ED), 20 cases of OSCC and 28 cases from patients who progressed from ED to OSCC) to determine the overall validity of the approach and establish cut off values. Results There was a significant and progressive increase in the colocalization of invadopodia markers (HIT score) in dysplasias and OSCC compared to control. The results showed that the HIT score could detect lesions that transformed to OSCC independently of the histopathological diagnosis with a sensitivity of 84% and specificity of 61.76%, PPV= 0.61 and NPV=0.84, AUC= 0.7653, likelihood ratio of 2.1, p Conclusion The HIT scores can predict malignant transformation in oral biopsies independent of the histopathological diagnosis. Larger prospective studies are needed to validate and assess the applicability of this test in combination with conventional histopathology.

Systematic approach for enrichment of docking outcome using consensus scoring functions

Traditional drug discovery is an expensive and time consuming process. Pharmaceutical industry suffers from a huge attrition due to last stage failure in traditional drug discovery. Bioinformatics principles can be utilized to overcome this pressure and speedup the process of drug discovery. Computer aided drug design is a remedy to avoid this loss. Drug design means designing the ligand that has high affinity towards target protein. This can be achieved by Virtual Screening. Ligand based virtual screening utilizes information from the ligand about the target. It is a ligand centric approach. The availability of three dimensional structures of protein targets and their possible ligands are utilized for identification and optimization of lead molecules (positive hits) in Structure based virtual screening. It is a target centric approach. To find out fit poses of ligand and its affinity at the active site of target Molecular Docking is done. Molecular docking is tool that contains search algorithm and scoring function. Search algorithms predict the binding modes of a target and fit ligand conformations towards the target. Scoring function is involved in prediction of the affinity of a ligand to bind to a protein target. There are various plat forms and scoring functions for predicting ligand – protein interactions. Consensus Scoring is a technique of combing information from multiple scoring functions and gives relatively accurate result when compared to single scoring function. It shows improvement in terms of quality of hit scores, false positive rate and enrichment. Consensus Scoring gives better, accurate and consistent results across the receptor systems when compared to individual or single scoring functions.

Incidence of intimate partner violence among Ugandan women with pelvic floor dysfunction.

To assess the occurrence of intimate partner violence (IPV) among women seeking surgery for pelvic floor dysfunction (PFD) in a rural African community. A prospective questionnaire-based study was conducted among women with obstetric fistula, unrepaired obstetric anal sphincter injuries (OASIS), or severe (stage 3 or 4) pelvic organ prolapse (POP) who attended surgical camps at Kagando Hospital in western Uganda between July 15, 2016, and September 14, 2017. The control group comprised women without PFD. Participants completed the Hurt, Insult, Threaten, and Scream (HITS) tool and the Woman Abuse Screening Tool (WAST) to screen for IPV. 117 of the 312 women interviewed reported current IPV: 73/214 (34.1%) in the PFD group and 44/98 (44.9%) in the control group. The PFD group comprised unrepaired OASIS (n=85, 39.7%), obstetric fistula (n=75, 35.1%), and severe POP (n=54, 25.2%). All groups experienced high levels of IPV. The frequency of positive screening results for IPV with WAST (score ≥13.0) and/or HITS (score ≥10.5) were: severe POP (n=17, 31.5%), obstetric fistula (n=28, 37.3%), unrepaired OASIS (n=30, 35.3%), and control group (n=44, 44.9%). Women in western Uganda experienced high rates of IPV, regardless of whether or not they had PFD. ANZCTR number: ACTRN12617001073392.

Enhancing Molecular Promiscuity Evaluation Through Assay Profiles.

The growing amount of heterogeneous bioactivity data requires effective strategies to assess the promiscuity/selectivity of small-molecules and aid drug discovery. In the current study, we aim to evaluate the potential of assay profiles (APs, i.e., unique combinations of assay-related features describing how activity determinations were performed and reported) in molecular promiscuity analysis. Using PubChem bioactivity data, we computed for all Molecular Libraries Small Molecule Repository (MLSMR library) compounds the frequency of hits score (FoH, i.e., the ratio between the number of times the compound was found active and the number of times it was tested), which were subsequently fit into 32 theoretical APs. The promiscuity of drugs and non-drugs was compared at different levels of test results. We found 8 dominant APs, indicating that compounds tested in more than ten assays (or against ten targets) and found active at least once tend to reach near to maximum hit rates in scientific literature and confirmatory assays (e.g., 95% of the drugs show FoH scores >0.93). Primary and high-throughput screening testing results in very low hit rates (e.g., 95% of the compounds show FoH scores <0.11), promoting a different perspective of promiscuity. In general, drugs exert higher promiscuity compared to non-drugs. Targets and classes of drugs are also discussed within the main APs. APs contain relevant features and are suited for big data promiscuity analysis. The activity data of the main APs are freely available on www.chembioinf.ro .

Application of Artificial Neural Networks to Rainfall Forecasting in the Geum River Basin, Korea

This study develops a late spring-early summer rainfall forecasting model using an artificial neural network (ANN) for the Geum River Basin in South Korea. After identifying the lagged correlation between climate indices and the rainfall amount in May and June, 11 significant input variables were selected for the preliminary ANN structure. From quantification of the relative importance of the input variables, the lagged climate indices of East Atlantic Pattern (EA), North Atlantic Oscillation (NAO), Pacific Decadal Oscillation (PDO), East Pacific/North Pacific Oscillation (EP/NP), and Tropical Northern Atlantic Index (TNA) were identified as significant predictors and were used to construct a much simpler ANN model. The final best ANN model, with five input variables, showed acceptable performance with relative root mean square errors of 25.84%, 32.72%, and 34.75% for training, validation, and testing data sets, respectively. The hit score, which is the number of hit years divided by the total number of years, was more than 60%, which indicates that the ANN model successfully predicts rainfall in the study area. The developed ANN model, incorporated with lagged global climate indices, could allow for more timely and flexible management of water resources and better preparation against potential droughts in the study region.

Effects of health information technology and health information exchanges on readmissions and length of stay

IntroductionThis study explored the effects of HIT/HIE on the outcomes and quality of care for diabetes, asthma, acute myocardial infarction, congestive heart failure, and hip and knee fracture. 30 day readmissions and average length of stay were used as measures of quality of care. MethodsThis study used the HIMSS IT database, coupled with the American Hospital Association (AHA) Hospital survey data and the CMS outpatient and skilled nursing facility Medicare claims data from 2006–2012, along with the standard Medicare file of patient claims for 2006–2012 as the control cohort. Using heirarchical clustering analysis methods, we construct HIT scores for measures of HIT and HIE implementation and penetration across 32 measures of HIT adoption. The scores are then used as the coefficient of interest using fixed effects methods and multinomial regressions, controlling for hospital and patient characteristics, as well as time-invariant factors. ResultsThis study finds that those institutions with the highest HIT scores for specific measures of clinical decision support, continuity of care documentation and clinical discharge and summary care documentation showed modest and statistically significant reduction in 30 day readmissions, with no effects on length of stay. DiscussionThis study has major implications for the future of HIT/HIE in coordinating care across disparate entities. Initiatives aimed at improving care coordination, fostering health ecosystems, and reducing costs associated with unnecessary readmissions and length of stay and stand to benefit from this research in that it highlights tangible areas where HIT/HIE participation may be beneficial to achieving improved health.

Estimation of the added value of using rainfall–runoff transformation and statistical models for seasonal streamflow forecasting

ABSTRACTTwo methods for generating streamflow forecasts in a Sahelian watershed, the Sirba basin, were compared. The direct method used a linear relationship to relate sea-surface temperature to annual streamflow, and then disaggregated on a monthly time scale. The indirect method used a linear relationship to generate annual precipitation forecasts, a temporal disaggregation to generate daily precipitation and the SWAT (Soil and Water Assessment Tool) model to generate monthly streamflow. The accuracy of the forecasts was assessed using the coefficient of determination, the Nash-Sutcliffe coefficient and the Hit score, and their economic value was evaluated using the cost/loss ratio method. The results revealed that the indirect method was slightly more effective than the direct method. However, the direct method achieved higher economic value in the majority of cost/loss situations, allowed for predictions with longer lead times and required less information.

Discovering Top Experts for Trending Domains on Stack Overflow

Stack Overflow is an online Question Answer Community, generating huge user content for research analysis. Stack Overflow is used to find top experts on a specific domain. The domains of interest are java, javascript, C# and python. The study identifies topic specific expert as with the Stack Overflow statistics, where the latter provides top experts based on reputation score irrespective of the domain. The algorithms used are PageRank and HITS score. The Discounted Cumulative Gain is used to measure the correctness of the analysis.

Effectiveness Of Identifying A Cancer Patient In The Hospital Sector In Northern-Norway - Analyses Based On Updated Regional Performance Database

Implementing a Danish model, Norway introduced 28 standardized diagnostic pathways (SDPs) in 2015 for patients suspected to have a malignancy. Authors evaluate the development of main indicators of SPDs and present the effectiveness of identifying a cancer patient by using SPDs in a secondary health care environment. The Northern-Norway Regional Health Authority Trust established a database collecting relevant information from electronic patient journals in all hospitals of the region according to SPDs (procedures, time stamps, medical decisions). All data recorded in the database has been anonymized. Data for patients who entered the secondary healthcare in 2015 and in 2016 were selected and analyzed. SAS software tools (Enterprise Guide 7.1, Visual Analytics 7.3) and MS Excel 2013 were used for data processing, analyses and visualization. A total number of 10232 (100%) diagnostic cancer pathway cases were initiated in 2015 and in 2016. 78,38% of all identified cancer cases in 2015 and 2016 (5781) were diagnosed by pathway activities. 68,94% of all fulfilled pathways (9781, 95,6%) were completed within national standard time intervals. Drop-out rate was 2,77%, in 50,85% cases the suspect of cancer was not confirmed, and 46,38% were identified as proven cancer patients. Effectiveness of pathways were estimated by the ratio of confirmed/unconfirmed cases in all pathways. This ratio varies from 9% (SDP-sarcomas, N=33) til 95% (cancer of the uterus N=122). Introduction of special and prioritized SPDs provide a good tool for monitoring and improving the quality of diagnostic processes. Two years after introduction of SPDs – not surprisingly – there is still wide range of variations in effectiveness. The evaluation of process indicators (pathways completed within national standard time; hit score) can be used to identify bottlenecks, identify variations in processes in order to increase effectiveness, subsequently avoiding unnecessary activities, risks and costs.

Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies

In the present work, multiple pharmacophore-based virtual screening of the SPECS natural product database was carried out to identify novel inhibitors of the validated biological target, InhA. The pharmacophore models were built from the five different groups of the co-crystallized ligands present within the active site. The generated models with the same features from each group were pooled and subjected to the test set validation, receiver–operator characteristic analysis and Güner–Henry studies. A set of five hypotheses with sensitivity > 0.5, specificity > 0.5, area under curve (AUC) > 0.7, and goodness of hit score > 0.7 were retrieved and exploited for the virtual screening. The common hits (87 molecules) obtained from these hypotheses were processed via drug-likeness filters. The filtered molecules (27 molecules) were compared for the binding modes and the top scored molecules (12 molecules) along with the reference (triclosan (TCL), docking score = −11.65 kcal/mol) were rescored and reprioritized via molecular mechanics-generalized Born surface area approach. Eventually, the stability of reprioritized (10 molecules) docked complexes was scrutinized via molecular dynamics simulations. Moreover, the quantum chemical studies of the dynamically stable compounds (9 molecules) were performed to understand structural features essential for the activity. Overall, the protocol resulted in the recognition of nine lead compounds that can be targeted against InhA.

In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs

ObjectiveExplicating the property and action of traditional Chinese medicine (TCM) in the perspectives of modern science deepens the insight into the property of TCM, and provides the basis for new drug discovery and clinical therapy. In this study, we investigated the relationship between transient receptor potential melastatin 8 (TRPM8) and pungent flavor using three-dimensional pharmacophores based on virtual screening methods. MethodsFirstly, an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation. Then, several therapeutic targets, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), cholesteryl ester transfer protein (CETP), Niemann-Pick C1-Like 1 (NPC1L1) and platelet-activating factor receptor (PAFR), were selected to screen traditional Chinese herbs, and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets. ResultsAccording to the screening results, TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8, which shares the common virtual screening hits with the therapeutic targets, was considered to be related to the action of pungent taste. ConclusionThe novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.

Primary cutaneous B‐cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers

Categorization of primary cutaneous B‐cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus‐based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL‐LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL‐NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a “double hit score” upon positivity for BCL2 and MYC. PCDLBCL‐NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B‐cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a “non‐germinal B‐cell” profile, whereas “germinal center” cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC‐LT, which often coexpressed MYC and BCL2. The impact of single factors on 5‐year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group—PCDLBCL‐NOS—exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.

Cross–Time Scale Interactions and Rainfall Extreme Events in Southeastern South America for the Austral Summer. Part II: Predictive Skill

Abstract Potential and real predictive skill of the frequency of extreme rainfall in southeastern South America for the December–February season are evaluated in this paper, finding evidence indicating that mechanisms of climate variability at one time scale contribute to the predictability at another scale; that is, taking into account the interference of different potential sources of predictability at different time scales increases the predictive skill. Part I of this study suggested that a set of daily atmospheric circulation regimes, or weather types, was sensitive to these cross–time scale interferences, conducive to the occurrence of extreme rainfall events in the region, and could be used as a potential predictor. At seasonal scale, a combination of those weather types indeed tends to outperform all the other candidate predictors explored (i.e., sea surface temperature patterns, phases of the Madden–Julian oscillation, and combinations of both). Spatially averaged Kendall’s τ improvements of 43% for the potential predictability and 23% for real-time predictions are attained with respect to standard models considering sea surface temperature fields alone. A new subseasonal-to-seasonal predictive methodology for extreme rainfall events is proposed based on probability forecasts of seasonal sequences of these weather types. The cross-validated real-time skill of the new probabilistic approach, as measured by the hit score and the Heidke skill score, is on the order of twice that associated with climatological values. The approach is designed to offer useful subseasonal-to-seasonal climate information to decision-makers interested not only in how many extreme events will happen in the season but also in how, when, and where those events will probably occur.

Increasing the performance of pooled CRISPR-Cas9 drop-out screening.

Components of the type II CRISPR–Cas complex in bacteria have been used successfully in eukaryotic cells to facilitate rapid and accurate cell line engineering, animal model generation and functional genomic screens. Such developments are providing new opportunities for drug target identification and validation, particularly with the application of pooled genetic screening. As CRISPR–Cas is a relatively new genetic screening tool, it is important to assess its functionality in a number of different cell lines and to analyse potential improvements that might increase the sensitivity of a given screen. To examine critical aspects of screening quality, we constructed ultra-complex libraries containing sgRNA sequences targeting a collection of essential genes. We examined the performance of screening in both haploid and hypotriploid cell lines, using two alternative guide design algorithms and two tracrRNA variants in a time-resolved analysis. Our data indicate that a simple adaptation of the tracrRNA substantially improves the robustness of guide loss during a screen. This modification minimises the requirement for high numbers of sgRNAs targeting each gene, increasing hit scoring and creating a powerful new platform for successful screening.

The prognostic impact of serum albumin in double hit/double expressing aggressive B cell lymphomas: A pilot study evaluating SAAB scoring system.

e19044Background: Double hit lymphomas (DHL) [rearrangements of MYC and BCL2/BCL6, and double expressing lymphomas (DEL) [expression of MYC and BCL6/BCL2 by immunohistochemistry] represent a subset of diffuse large B-cell lymphoma (DLBCL) with poor overall survival (OS). Several prognostic scores have been tested to clinically stratify these patients with the double hit score (DHS) being the most recently developed model (Petrich 2014). We explored the use of serum albumin (SA) as prognostic factor in DHL as previously shown in DLBCL (Dalia 2013). Methods: We included 100 patients from Moffitt Cancer Center database from January 2008 to December 2015 with DHL and performed a retrospective chart review. Recorded clinical data included SA, hemoglobin, age, International Prognostic Index (IPI), DHS, and lymphopenia. Pairwise Cox Comparison was used to develop a weighted scoring system. Kaplan-Meier method with Cox proportional hazard model was used to determine OS. Results: The median age was 63 (18-87), sta...

Clinicopathological prognostic factors of 24 patients with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (iBL/DLBCL), is a rare, but an aggressive subtype. In iBL/DLBCL, clinicopathological prognostic factors, including MYC and BCL2 translocations (double hit translocation, DHT) and the expression of both MYC and BCL2 (double hit score 2, DHS2), have not been studied thoroughly. We retrospectively analyzed the prognostic impact of clinicopathological factors, including MYC split, IGH/BCL2 fusion, MYC and BCL2 expressions, in 24 iBL/DLBCL patients (median age: 47years). Fifteen patients (62%) underwent intensive chemotherapy, and nine patients (38%) underwent rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The 5-year progression-free (PFS) and overall survival (OS) rates of intensive chemotherapy and R-CHOP were 57 and 72%, respectively. PFS was significantly shorter in patients with high IPI score (P<.0001), stage IV (P=.001), aged ≥60years (P=.042), IGH/BCL2 fusion (P=.029), DHS2 (P=.015), and DHT (P=.03). OS was significantly shorter in patients with high IPI score (P<.0001) and aged ≥60years (P=.008). In iBL/DLBCL, IGH/BCL2 fusion, DHS2, and DHT were pathological prognostic factors for poor PFS, while IPI remained as more predictive for PFS and OS.

Seasonal forecasting of tropical cyclogenesis over the North Indian Ocean

Over the North Indian Ocean (NIO) and particularly over the Bay of Bengal (BoB), the post-monsoon season from October to December (OND) are known to produce tropical cyclones, which cause damage to life and property over India and many neighbouring countries. The variability of frequency of cyclonic disturbances (CDs) during OND season is found to be associated with variability of previous large-scale features during monsoon season from June to September, which is used to develop seasonal forecast model of CDs frequency over the BoB and NIO based on principal component regression (PCR). Six dynamical/thermodynamical parameters during previous June–August, viz., (i) sea surface temperature (SST) over the equatorial central Pacific, (ii) sea level pressure (SLP) over the southeastern equatorial Indian Ocean, (iii) meridional wind over the eastern equatorial Indian Ocean at 850 hPa, (iv) strength of upper level easterly, (v) strength of monsoon westerly over North Indian Ocean at 850 hPa, and (vi) SST over the northwest Pacific having significant and stable relationship with CDs over BoB in subsequent OND season are used in PCR model for a training period of 40 years (1971–2010) and the latest four years (2011–2014) are used for validation. The PCR model indicates highly significant correlation coefficient of 0.77 (0.76) between forecast and observed frequency of CD over the BoB (NIO) for the whole period of 44 years and is associated with the root mean square error and mean absolute error ≤ 1 CD. With respect to the category forecast of CD frequency over BoB and NIO, the Hit score is found to be about 63% and the Relative Operating Curves (ROC) for above and below normal forecast is found to be having much better forecast skill than the climatology. The PCR model performs very well, particularly for the above and below normal CD year over the BoB and the NIO, during the test period from 2011 to 2014.