Pavithran Keechilat

Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine.

UNLABELLED Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. FROM THE CLINICAL EDITOR These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use.

Epidermal growth factor receptor (EGFR) structure-based bioactive pharmacophore models for identifying next-generation inhibitors against clinically relevant EGFR mutations.

Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure‐based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three‐dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors), that is, one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings. Pharmacophore models were validated using decoy dataset, Receiver operating characteristic plot, and external dataset compounds. The robust, bioactive 3D e‐pharmacophore models were then used for VS of four different small compound databases: FDA approved, investigational, anticancer, and bioactive compounds collections of Selleck Chemicals. CUDC101 a multitargeted kinase inhibitor showed highest binding free energy and 3D pharmacophore fit value than the well known EGFR inhibitors, Gefitinib and Erlotinib. Further, we obtained ML167 as the second best hit on VS from bioactive database showing high binding energy and pharmacophore fit value with respect to EGFR receptor and its mutants. Optimistically, presented drug discovery based on the computational study serves as a foundation in identifying and designing of more potent EGFR next‐generation kinase inhibitors and warrants further experimental studies to fight against lung cancer.

Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data.

AIM Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations. MATERIALS & METHODS Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Independent evaluation was performed in a small cohort of patients. RESULTS Our analysis revealed significant differences in the the allelic distribution of variants in different ethnicities. CONCLUSIONS This is the first and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies.

Robot-assisted supine extraperitoneal retroperitoneal lymph node dissection: a novel approach for template dissection in post-chemotherapy residual mass in non-seminomatous germ cell tumours

Robot-assisted retroperitoneal lymph node dissection (RA-RPLND) in testicular cancer is conventionally performed through transperitoneal route. We report a case of robot-assisted supine extraperitoneal RPLND (RASE-RPLND), not previously described in the literature, which was performed for post-chemotherapy residual mass in a case of non-seminomatous germ cell tumour (NSGCT). RASE-RPLND apart from providing the benefits of robotic assistance has a significant advantage over transperitoneal approach, as the procedure can be performed in supine position without any bowel handling. Herein, we provide a detailed description of the novel surgical technique employed by us in this case.

Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion

Advanced nonsmall cell lung cancer (NSCLC) treatment is primarily based on platinum-based chemotherapy. Although epidermal growth factor receptor (EGFR) targeting has shifted the treatment paradigm toward personalized tyrosine kinase inhibitors (TKIs), resistance develops inevitably and EGFR T790M is the most common acquired resistance mechanism. Rebiopsy of resistant NSCLC cases can provide additional information on the underlying resistant mechanisms and therefore can help clinicians in taking better management decisions. An expert panel meeting of renowned cancer oncologists was held to discuss the management of advanced-stage NSCLC. The present paper is based on the recommendations made by the expert panel and is supported by an exhaustive literature search. It was suggested that identification of driver mutation leads to better treatment decisions. TKIs have proven to be better treatment option in EGFR-positive patients as compared to chemotherapy. Third-generation TKIs (osimertinib) promise to bring optimal and improved care for NSCLC cases failing first-line TKI treatment.

Pathological profile of lymphomas in a tertiary care centre in Kerala

To the Editor: Lymphomas constitute 4–5% of all malignancies. There has been an increasing incidence of lymphomas worldwide in the past few decades, but the frequency and pattern varies in different geographic regions. In India its incidence is on the upsurge with the current figure standing at 5.1 per 100 000 in urban registries. Our study was done to: (i) find out the overall incidence of lymphomas among the patients with malignancies who attended our institute; (ii) subtype lymphomas based on morphology and immunohistochemistry according to the World Health Organization (WHO) (2001 and 2008) classification; and (iii) correlate the pathological features with clinical profiles. This is a retrospective analysis of all proved cases of lymphoma confirmed by immunohistochemistry (IHC) seen in the departments of Medical Oncology and Pathology at Amrita Institute of Medical Sciences during the 3 year period between January 2007 and December 2009. In all cases, routine HE sections were studied and based on morphological diagnosis, IHC lymphoma panel was selected from among the following antibodies: LCA, CD3, CD20, CD45RO, CD79a, CD15, CD30, EMA, ALK, CD68, S100, CD138, kappa, lambda, Bcl2, CD5,CD 10,CD 23, Cyclin D1, Tdt*,CD 99 and Ki 67 (prediluted antibodies, Biogenex Laboratories, San Ramon, CA, USA; Dako Laboratories, Carpinteria, CA, USA). Clinical details were collected from the electronic medical records. In cases where patients have not visited the clinic recently, they were contacted by telephone and the latest follow up details were collected. Lymphomas were classified into Hodgkin’s (HD) or nonHodgkin’s (NHL) and further sub-typed based on WHO (2001 and 2008) classification. Complete staging workup including bone marrow study was done in all cases. The minimum follow up period was 6 months. There were 431 new cases of lymphoma, which constituted 4.9% of all malignancies (431/ 8712) reported from the department of Pathology during the 3 year period. Median age was 47.5 years (range 4 to 87). There were 287 males and 144 females, with a male predominance (66.8%). Nodal lymphomas constituted the most common group (74%) of cases, with cervical lymph node being the most common biopsied site. Among the extranodal sites (Table 1), gastrointestinal tract (25%), bone (9%) and skin (8%) were the common sites. 355 (82%) cases were non-Hodgkin’s lymphoma, of which 73% were of B cell type and 26% were of T cell type. Null cell type contributed only to 1%. Among the B cell lymphomas (Table 2), diffuse large B cell lymphoma (DLBL) was the single most common subgroup (59%), the remaining were follicular (15%), followed by others like mantle cell lymphoma (12%), B lymphoblastic (9.3%), Burkitts lymphoma (3%) and marginal zone lymphoma (0.5%). A few (1.2%) were left as unclassified low grade cases, as a complete immunohistochemical panel could not be done. Among the T lymphomas (Table 2), 19% were lymphoblastic and the rest were all mature T cell lymphomas, which included anaplastic large cell lymphoma (ALCL) (33%), peripheral T cell lymphoma (PTCL) (29%) and cutaneous T cell lymphoma (CTCL) (19%). Hodgkin’s lymphomas constituted 18% of total cases. Bone marrow involvement was seen in 105/431 (24%) cases. It was commonly seen in low grade lymphomas (40%) followed by DLBL (26%). 10% of Hodgkin’s lymphomas showed marrow involvement. Non-Hodgkin’s lymphoma represents various lymphoid malignancies with diverse clinicopathological and biological characteristics. Based on most of the studies conducted among the Western population, including the statistical analysis mentioned in the WHO classification of tumors of hematopoietic and lymphoid tissue, 2008, 70% of lymphomas were of NHL type. However, variations in the incidence have been found in different geographic regions. 82% of cases in the present study were NHL, as against the Western data. This is in concordance with the incidence in other Asian countries like China. Similarly the occurrence of Hodgkin’s lymphoma is lesser (18%) when compared with Western populations, as is well documented. But in countries like Japan the incidence is only around 4.4%, which is much lower when compared with our population. The consistently low rates of HD in Asian people suggest genetic resistance to disease development, possibly associated with human leukocyte antigen (HLA) type. DLBL was the single most common lymphoma subset in the present series. This is comparable with the incidence of lymphomas mentioned in the study done by Naresh et al. According to WHO, DLBL and follicular lymphoma (FL) together contribute to the most common subtype. This also confirms the lower incidence of follicular lymphoma among Asian populations. This has been attributed to the significantly lower incidence of bcl-2 translocation in FL in the Asians when compared with the Western patients. bs_bs_banner