Abstract Background Wearable devices have developed the capacity to offer single-lead ECG analysis and are already widespread in use, particularly for detection of atrial fibrillation (1,2). Vectorcardiography entails the transformation of electrical vectors into X, Y, and Z axes to constitute a vectorcardiogram (VCG) (3). The VCG has diagnostic promise given the capacity to generate it without requiring clinical presentation for standard 12-lead ECG acquisition. Furthermore, a novel credit-card sized device capable of acquiring a VCG has recently been developed – raising the potential for arrhythmia detection and discrimination beyond wearable single-lead ECG systems. Objective To assess the performance of a deep learning algorithm trained on single lead and 12-lead ECGs and VCGs for detecting atrial flutter. Methods A convolutional neural network (AFL-CNN) was developed on a dataset of 4,000 ECGs and VCGs from a single US academic medical institution (80% training and 20% for testing). Validation was performed on a separate publicly available dataset (2223 ECGs). Model performance was assessed on single lead ECG analysis (lead I, obtained by removing the other leads) and standard 12-lead ECG. The gold standard for AFL diagnosis was physician-confirmed 12-lead ECG diagnoses in the dataset. The VCG was generated from the 12-lead ECG via Kors transformation matrix to which AFL-CNN was also applied. Model performance was assessed with sensitivity, specificity, positive and negative predictive values, accuracy, and F1 statistic. Results On single lead ECG analysis, AFL-CNN achieved 71.2% sensitivity and 96.9% specificity with PPV 84.0% and NPV 93.7% and 92.2% accuracy with F1 83.2%. When AFL-CNN was applied to the VCG, performance improved: 91.0% sensitivity and 98.7% specificity, PPV 94.24%, NPV 98.0%, 97.3% accuracy, and F1 95.31%. Lastly, the performance remained high when AFL-CNN was applied to the 12-lead ECG: 95.4% sensitivity, 98.63% specificity, PPV 94.0%, NPV 99.0%, and accuracy of 98.0%, with F1 97.2%. Conclusion A deep learning algorithm applied to vectorcardiography for the detection of atrial flutter showed improved performance over single lead analysis and comparable performance to standard 12-lead applications. The finding of improved model performance beyond single lead ECG tracings underscores both the limitations of current wearable technologies in arrhythmia detection beyond atrial fibrillation and the potential for VCG-based algorithm prediction to fill gaps in healthcare inequality when standard 12-lead acquisition is challenging to obtain.

Background Refractory cancers pose formidable management challenges. We hypothesized that such malignancies have unexplored vulnerabilities that can be identified using Encyclopedic Tumor Analysis (ETA) and effectively targeted using conventional agents in a label- and organ-agnostic manner to yield treatment benefit. The pan-cancer RESILIENT trial addressed patients with advanced refractory malignancies who were treated with ETA guided treatments regimens without any restrictive eligibility criteria. Methods Molecular Profiling (MP) of patients’ fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify molecular targets of approved anticancer agents in a label-agnostic manner. Immunohistochemistry (IHC) identified hormone receptors (HR) that could be targeted with endocrine agents. Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified functional vulnerabilities of the tumor against a panel of systemic anticancer agents. Synergistic integration of MP, IHC and CRR datasets (i.e., ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scans to determine treatment response as well as Objective Response Rate (ORR), Disease Control Rate (DCR) and Progression Free Survival (PFS). Results Among the 200 patients who were screened, 110 patients received ETA-guided treatments and were evaluable for response per protocol. PR was observed in 47 patients (ORR = 42.7%) and 99 patients continued to exhibit PR or SD at study termination (DCR = 90%). Median PFS was 125 days. Median PFS rate at 90 days was 94.0%. No significant therapy related adverse events (AEs) were noted – there were no grade IV AEs or treatment related deaths. Most patients reported stable to improved Quality of Life (QoL) in terms of disease-related symptoms and functional status. Conclusions ETA-guided treatments offer meaningful survival benefits and outperformed available alternatives including checkpoint inhibitors in this heavily pretreated pan-cancer population. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.

Background Though mTOR inhibition is considered an attractive strategy for cancer management, anti-mTOR monotherapies have not shown meaningful benefits. We hypothesized that an Encyclopedic Tumor Analysis (ETA) can identify vulnerabilities in the tumor in addition to mTOR activation. We further hypothesized that tandem synergistic targeting of these vulnerabilities using combination of mTOR inhibitors and other systemic anticancer agents in a label- and organ-agnostic manner can improve outcomes in refractory solid organ cancers as compared to mTOR inhibition monotherapy alone. Methods Molecular Profiling (MP) of patients’ fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify druggable molecular targets in a label-agnostic manner. Immunohistochemistry (IHC) identified targetable hormone receptors (HR). Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified vulnerabilities of the tumor against a panel of systemic anticancer agents. Molecular indications linked to PIK3CA, mTOR, PTEN or TP53 genes were used for selection of mTOR inhibitors. Synergistic integration of MP, IHC and CRR datasets (i.e., ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scan to determine treatment response. Results Among 41 patients who received combination treatments, 23 patients showed PR (ORR = 56.1%), 16 showed SD (DCR = 95.1%) and progression was observed in 2 patients. One patient who received monotherapy progressed at 27 days. Median PFS was 110 days (range 27 to 592). In the SHIVA trial where patients with mTOR activation (n = 46) received monotherapy with mTOR inhibitor, median PFS of 72 days (range 57 to 100) was reported. No significant therapy–related adverse events were reported in any patient. Most patients reported stable to improved Quality of Life (QoL). Conclusions ETA-guided combination regimens with mTOR inhibitors offer a viable and efficient strategy in advanced refractory malignancies and outperform mTOR inhibitor monotherapy. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.

Abstract Background Hormone and Growth Factor Receptors (HR) such as ER, PR, HER2 and AR are involved in the pathogenesis of various cancers and are commonly targeted in treatment regimens. HR antagonists Standard of Care (SoC) are often administered as monotherapy or as combinations with selected cytotoxic or targeted agents. In the SHIVA trial, monotherapy with HR antagonists based on molecular profiling was reported with dismal outcomes. We hypothesized that Encyclopedic Tumor Analysis (ETA)-informed novel combinations of HR and synergistic cytotoxic or targeted agents could be efficacious in multiple cancers. Methods Molecular Profiling (MP) of patients’ fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify molecular targets of approved anticancer agents in a label-agnostic manner. Immunohistochemistry (IHC) identified hormone receptors (HR) that could be targeted with endocrine agents. Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified functional vulnerabilities of the tumor against a panel of systemic anticancer agents. Molecular indications linked to ER, PR, HER2 and AR as well as IHC findings were linked to selection of HR antagonists. Synergistic integration of MP, IHC and CRR data (i.e., ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scans to determine treatment response. Results 37 patients underwent ETA from the study sponsor and received ETA-guided combination treatments of HR antagonists with other agents. PR was seen in 17 patients (ORR = 45.9%). 32 patients showed PR or SD at most recent follow-up (DCR = 86.5%) and progression was seen in 5 patients. Median PFS was 147 days (range 31 to 410). No significant therapy related adverse events were observed in any of these patients. Most patients reported stable to improved Quality of Life (QoL). Conclusions ETA-guided combination treatment regimens with HR antagonists offer a viable and efficient strategy in advanced refractory malignancies and outperform monotherapy options. Legal entity responsible for the study The Authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. C. Sims: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.

Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. The use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. Expert oncologist discussed about strategies of gene expression assays and aid in chemotherapy recommendations for treatment of HR + ve EBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

Paraneoplastic syndromes are common in mesotheliomas but there is no report from India. Two cases of pleural mesothelioma with paraneoplastic haematologic syndromes, one with neutrophilic leukemoid reaction and the other with thrombocytosis, are presented in this report. [Indian J Chest Dis Allied Sci 2009;51:185-188]

The role of palliative chemotherapy in Gallbladder Cancer (GBC) has been studied in multiple phase II trials utilizing various drugs like 5 Flourouracil, Cisplatin, Gemcitabine, etc. as single agents and in combinations. Most trials have combined biliary tract cholangiocarcinomas along with gallbladder adenocarcinomas. The prognosis and response among these two groups varies enough to warrant focused research on GBC. The available data points towards a role of chemotherapy in GBC. Further research is needed to study the impact of chemotherapy in overall survival, and quality of life in inoperable disease; and to define the role of adjuvant chemotherapy in a subset of patients with operable disease. The optimal choice of chemotherapeutic agents, also needs to be defined.

Specific cellular binding proteins for retinol and retinoic acid from mammalian and avian species may mediate the action of retinoids in the control of epithelial differentiation, growth and tumorigenesis. Parasite retinol-binding protein (PRBP) and parasite retinoic acid-binding protein (PRABP) isolated and characterized from parasitic worms of the family Filarioidea might be involved in some possible action of vitamin A compounds in these parasites. Ivermectin, a potent and widely used anti-parasitic drug, competes efficiently with retinol for retinol-binding sites on PRBP, but not for the host-tissue retinol-binding-protein sites. The drug has no affinity for retinoic acid-binding proteins from either parasite or host tissues. Binding studies using radiolabelled ivermectin and retinol reveal that ivermectin has a higher affinity than retinol for PRBP. A correlation exists between the binding affinities of ivermectin analogues and their anti-parasitic activities. A binding-protein-mediated interrelationship may exist between the actions of retinol and ivermectin in the parasites, but not in the host tissues.

The external segment of the T4 (CD4) glycoprotein functions as the T-cell surface receptor for human immunodeficiency virus by binding the major viral coat protein (gp120) with relatively high affinity. To more precisely define the region of T4 involved in gp120 interaction, we used purified, soluble forms of T4 anchor-minus polypeptides (produced in a baculovirus system) in conjunction with proteolytic fragmentation, microsequencing, and a specific T4-gp120 binding assay. The results indicate that the NH2-terminal region of T4 including the immunoglobulin variable-region-like domain is required for gp120 interaction. In contrast, the COOH-terminal half of the molecule, containing the two potential N-linked glycosylation sites, is not necessary. Furthermore, reduction of intrachain disulfide bonds in the T4 molecular abrogates gp120 binding, thereby strongly implying that the binding site for gp120 is dependent on the stabilized domain structure of the active binding region.

5'-Bromoacetamido-5'-deoxythymidine (BAT), 5'-iodoacetamido-5'-deoxythymidine (IAT), 5'-chloroacetamido-5'-deoxythymidine (CAT) and [14C]BAT were synthesized and their interactions with thymidylate synthase purified from L1210 cells were investigated. The inhibitory effects of these compounds on thymidylate synthase were in the order BAT greater than IAT greater than CAT, which is in agreement with their cytotoxic effects in L1210 cells. In the presence of substrate during preincubation, the concentration required for 50% inhibition of the enzyme activity by these inhibitors was 4-8-fold higher than it was in the absence of dUMP. The I50 values for BAT were 1 X 10(-5) M and 1.2 X 10(-6) M in the presence and absence, respectively, of dUMP during preincubation. These results were in agreement with the observed inhibition of thymidylate synthase by BAT in intact L1210 cells. A Lineweaver-Burk plot revealed that BAT behaved as a competitive inhibitor. The Km for the enzyme was 9.2 microM, and the Ki determined for competitive inhibition by BAT was 5.4 microM. Formation of a tight, irreversible complex is inferred from the finding that BAT-inactivation of thymidylate synthase was not reversible on prolonged dialysis and that the enzyme-BAT complex was nondissociable by gel filtration through a Sephadex G-25 column or by TSK-125 column chromatography. Incubation of thymidylate synthase with BAT resulted in time-dependent, irreversible loss of enzyme activity by first-order kinetics. The rate constant for inactivation was 0.4 min-1, and the steady-state constant of inactivation, Ki, was estimated to be 6.6 microM. The 5'-haloacetamido-5'-deoxythymidines provide specific inhibitors of thymidylate synthase that may also serve as reagents for studying the enzyme mechanism.

The present study deals with the discovery and partial characterization of specific binding proteins for retinol and retinoic acid from filarial parasites (worms of the superfamily Filarioidea), including those from two species of Onchocerca. These binding proteins, which are distinct in their physicochemical properties and in the mode of ligand interactions from the host-tissue retinoid-binding proteins, may be involved in the mediation of the putative biological roles of retinoids in the control of parasitic growth, differentiation and reproduction. Parasite retinol-binding protein and retinoic acid-binding protein exhibited specificity for binding retinol and retinoic acid respectively. Both the binding proteins showed an s20,w value of 2.0 S. On gel filtration, both proteins were retarded to a position corresponding to the same molecular size (19.0 kDa). On preparative columns, the parasite binding proteins exhibited isoelectric points at pH 5.7 and 5.75. Unlike the retinoid-binding proteins of mammalian and avian origin, the parasite retinoid-binding proteins showed a lack of mercurial sensitivity in ligand binding. The comparative amounts of retinoic acid-binding protein in five parasites, Onchocerca volvulus, Onchocerca gibsoni, Dipetalonema viteae, Brugia pahangi and Dirofilaria immitis, were between 2.7 and 3.1 pmol of retinoic acid bound/mg of extractable protein. However, the levels of parasite retinol-binding protein were between 4.8 and 5.8 pmol/mg, which is considerably higher than the corresponding levels of cellular retinol-binding protein of mammalian and avian origin. Both retinol- and retinoic acid-binding-protein levels in O. volvulus-infected human nodules and O. gibsoni-infected bovine nodules were similar to their levels in mammalian tissues. Also, these nodular binding proteins, like the host-binding proteins, exhibited mercurial sensitivity to ligand interactions.