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In the recent years, the reported cases of mitochondrial disorders have reached a colossal number. These disorders spawn a sundry of pathological conditions, which lead to pernicious symptoms and even fatality. Due to the unpredictable etiologies, mitochondrial diseases are putatively referred to as “mystondria” (mysterious diseases of mitochondria). Although present-day research has greatly improved our understanding of mitochondrial disorders, effective therapeutic interventions are still at the precursory stage. The conundrum becomes further complicated because these pathologies might occur due to either mitochondrial DNA (mtDNA) mutations or due to mutations in the nuclear DNA (nDNA), or both. While correcting nDNA mutations by using gene therapy (replacement of defective genes by delivering wild-type (WT) ones into the host cell, or silencing a dominant mutant allele that is pathogenic) has emerged as a promising strategy to address some mitochondrial diseases, the complications in correcting the defects of mtDNA in order to renovate mitochondrial functions have remained a steep challenge. In this review, we focus specifically on the selective gene therapy strategies that have demonstrated prospects in targeting the pathological mutations in the mitochondrial genome, thereby treating mitochondrial ailments.

Sepsis is a grievous health concern with limited understanding of its precise etiology. Although studies on sepsis have implicated the Warburg effect (mitigation of mitochondrial oxidative phosphorylation, as evident from aerobic glycolysis), we propose that an evolutionary perspective might further unravel its etiology. The endosymbiotic theory suggests that evolution of a eukaryotic cell is a consequence of the fruitful association between an archaea (Asgard) and an alphaproteobacterium (Rickettsia). We hypothesize that, during pathological conditions like sepsis, such endosymbiotic homeostasis between the two systems is perturbed. We underscore the fact (supported by in silico homology analyses) that during sepsis, the Asgard component of a cell is promoted to trigger aerobic glycolysis as well as the innate immune response (spearheaded by the TLR pathway), while suppressing the Rickettsia counterpart, thereby promoting the Warburg effect. It might be this discord between the two endosymbiotic partners (Asgard and Rickettsia-derived cellular components) that promotes sepsis.

Cancer is a grievous concern to human health, owing to a massive heterogeneity in its cause and impact. Dysregulation (numerical, positional and/or structural) of centrosomes is one of the notable factors among those that promote onset and progression of cancers. In a normal dividing cell, a pair of centrosomes forms two poles, thereby governing the formation of a bipolar spindle assembly. A large number of cancer cells, however, harbor supernumerary centrosomes, which mimic the bipolar arrangement in normal cells by centrosome clustering (CC) into two opposite poles, thus developing a pseudo-bipolar spindle assembly. Manipulation of centrosome homeostasis is the paramount pre-requisite for the evasive strategy of CC in cancers. Out of the varied factors that uphold centrosome integrity, microtubule motors (MiMos) play a critical role. Categorized as dyneins and kinesins, MiMos are involved in cohesion of centrosomes, and also facilitate the maintenance of the numerical, positional and structural integrity of centrosomes. Herein, we elucidate the decisive mechanisms undertaken by MiMos to mediate centrosome homeostasis, and how dysregulation of the same might lead to CC in cancer cells. Understanding the impact of MiMos on CC might open up avenues toward a credible therapeutic target against diverse cancers.

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the 'route and reach' of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.

Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-MB-231). On 24 h treatment, the nID caused decline in the viability of MDA-MB-231 and MDA-MB-468 cells, but did not significantly (P 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-MB-231 and MDA-MB-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21

Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.

Chemotherapy is one of the most popular therapeutic strategies to treat cancer. However, cancer chemotherapeutics have often been associated with impairment of the immune system, which might consequently lead to an augmented risk of autoimmune disorders, such as rheumatoid arthritis. Though the accurate mechanistic facets of rheumatoid arthritis induction have not been interpreted yet, a conglomeration of genetic and environmental factors might promote its etiology. What makes the scenario more challenging is that patients with rheumatoid arthritis are at a significantly elevated risk of developing various types of cancer. It is intriguing to note that diverse cancer chemotherapy drugs are also commonly used to treat symptoms of rheumatoid arthritis. However, a colossal multitude of such cancer therapeutics has demonstrated highly varied results in rheumatoid arthritis patients, including both beneficial and adverse effects. Herein, we attempt to present a holistic account of the variegated modalities of this complex tripartite cross-talk between cancer, rheumatoid arthritis and chemotherapy drugs in order to decode the sinuous correlation between these two appalling pathological conditions.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.

Aims: The absolute white blood cell (WBC) count and neutrophil to lymphocyte (N/L) ratio are predictors of death/myocardial infarction in patients who have undergone coronary angiography. We hypothesized that a pre-procedural elevated WBC count and an elevated N/L ratio would be a predictor of development of significant ventricular arrhythmias in subjects undergoing percutaneous coronary intervention (PCI). Methods and Results: We retrieved the data for all patients developing ventricular arrhythmia during PCI between 1999 to 2009 from our cath lab database (from 30,798 records), a total of 70 patients (Group I), and tabulated their WBC counts and absolute neutrophil and lymphocyte counts as well as N/L ratios. We compared the data with a random group of age, gender, medications and pre-existing condition matched controls (n=70) (Group II). We also adjusted for amount of myocardium under jeopardy. Group I had a significantly higher total WBC count (means 14,344 Vs 6852; 95% CI; p=0.0004); neutrophil count (means 75.79% Vs 58.06%; 95% CI; p < 0.0001) and N/L ratio (means 3.79 Vs 1.56; 95% CI; p < 0.0001) [means compared with t test]. Conclusion: Our data suggests a pre-procedural elevated WBC count, neutrophils and elevated N/L ratio are predictors of significant ventricular arrhythmias in patients undergoing percutaneous coronary intervention (PCI).

Central nervous system (CNS) hemangiopericytomas are rare mesenchymal tumors of the brain. In the absence of randomized clinical trials or large studies, the only information we have about the natural history and the management is from isolated clinical case series. They have suggested that surgery is beneficial, with conflicting results on the role of complete resection and adjuvant radiation. We have conducted a systematic review of clinical case series of CNS hemangiopericytoma analyzing the biology of the tumor and the best follow-up and management strategy. Fifteen pertinent clinical case series on newly diagnosed CNS hemangiopericytoma were selected by a review of literature. A total of 523 patients were analyzed for age, sex, mode of recurrence and metastases, and survival after complete/incomplete resection with or without radiation. The mean age was found to be 44.17 (±3.59) years. The incidence was higher in male individuals younger than 45 years and in older female individuals. Complete resection and adjuvant radiation significantly improved survival in comparison with incomplete resection and no radiation, respectively (P

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although rare, can be devastating. Conflicting reports have been published regarding the protective effect of systemic rituximab therapy and likely reduction in incidence of CNS relapse in post-rituximab era. Methods: We retrospectively identified all the DLBCL patients at our institute between 2004 and 2014 who received systemic rituximab-based chemo-therapy at initial presentation. Patients were categorized into two groups, “standard risk” with no risk factors and “high risk” with one or more of the following risk factors, elevated lactate dehydrogenase (LDH) (above the institute normal), international prognostic index (IPI) ≥3, involvement of testis, breast, bone, kidneys, adrenal gland, retroperitoneal lymph nodes, para-meninges, and bone marrow. Descriptive statistics were used to analyze inci-dence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results: A total of 122 patients received rituximab-based therapy at the initial diagnosis; 73 patients (60%) qualified for standard risk; 49 patients (40%) met the criteria for “high risk” based on the above definition. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapse. Thirty-one of 49 (63%) “high risk” patients received CNS prophylaxis, mainly intrathecal (IT) methotrexate. Five patients (4.0%) developed CNS relapse in the entire study population. Percentage of patients developed CNS relapse in high-risk patients was 10.2% (5/49). Median time to relapse was 8.76 months and median survival after CNS relapse was 9.16 months. Four out of five patients who developed CNS relapse received prophylaxis with IT. Conclusions: CNS relapse continued to be a rare but devas-tating complication in post rituximab era, however our study confirms that majority of the DLBCL patients do not need CNS directed therapy. Current CNS directed therapies are probably inadequate to prevent CNS relapse in high risk DLBCL patients, therefore further research to develop better agents is needed in this area.

Hexavalent chromium Cr(VI) is a very strong oxidant which consequently causes high cytotoxicity through oxidative stress. Prevention of Cr(VI)-induced cellular damage has been sought in this study in aqueous and methanolic extracts ofLawsonia inermisLinn. (Lythraceae), commonly known asHenna. The extracts showed significant (P< .05) potential in scavenging free radicals (DPPH•and ABTS•+) and Fe3+, and in inhibiting lipid peroxidation. DNA damage caused by exposure of pBR322 to Cr(VI)-UV is markedly inhibited by both extracts in varying degrees. A distinct decline in Cr(VI)-induced cytotoxicity was noticed in MDA-MB-435S (human breast carcinoma) cells with an increase in dosage of both extracts individually. Furthermore, both extracts proved to contain a high content of phenolic compounds which were found to have a strong and significant (P< .05) positive correlation to the radical scavenging potential, lipid peroxidation inhibition capacity and cyto-protective efficiency against Cr(VI)-induced oxidative cellular damage. HPLC analysis identified some of the major phenolic compounds in both extracts, which might be responsible for the antioxidant potential and the properties of DNA and cyto-protection. This study contributes to the search for natural resources that might yield potent therapeutic drugs against Cr(VI)-induced oxidative cell damage.

Cyanthillium cinereum(Less.) H. Rob. (Asteraceae) has been traditionally known for its medicinal properties, all aspects of which are yet to be exploited. This study was aimed at investigating the therapeutic potential of polar (methanolic and aqueous) and nonpolar (hexane and chloroform) crude extracts of the whole plant. Several parameters including free-radical (DPPH•, ABTS•+, H2O2and•OH) scavenging, reducing power, protection of DNA against oxidative damage, cytotoxicity, inhibition of oxidative hemolysis in erythrocytes, total phenolic content and inhibition of lipid peroxidation were examined. All the free-radical generating assay models demonstrated positive scavenging efficiency with differential but considerable magnitudes for the four extracts. However, only the hexane extract showed significant H2O2scavenging effect. Lipid peroxidation was estimated by thiobarbituric acid-malondialdehyde (MDA) reaction, and a high degree of inhibition was shown by all the extracts. Reducing power of the polar extracts was higher than the non-polar ones. All extracts showed a concentration-dependent increase in phenolic contents. Oxidative damage to erythrocytes was hindered by all extracts in diverse degrees. XTT assay showed that all extracts have mild cytotoxic property. The aqueous extract evidently demonstrated protective effect on pBR322 plasmid DNA against oxidative breakdown. These results suggested the potential ofC. cinereumas medicine against free-radical-associated oxidative damage and related degenerative diseases involving metabolic stress, genotoxicity and cytotoxicity.

e19523 Gender specific mortality in diffuse large B cell lymphoma patients receiving R-CHOP Background: Significant gender specific mortality differences were observed in diffuse large B cell lymph...

INTRODUCTION CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy. METHOD Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords “CNS”, “diffuse large B-cell lymphoma”, “relapse”, “prophylaxis”, “rituximab”, “CHOP” were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P RESULTS The study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P CONCLUSION Rituximab hasn't significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era. Abstract 1644. TABLE STUDY Age (yr) Sex (M:F) No. Stage 3/4 IPI int-high/ high (>=3 IPI or >=2 aa IPI) Extranodal (>=2) high LDH Follow up (m) Criteria for CNS prophylaxis Patients receiving CNS prophylaxis (IT=intrathecal, S=systemic) Chemo Tilly 2003 61-69 ACVBP vs CHOP : M 182 vs 177 F 141 vs 135 635 (501 DLBCL) 267 vs 253 210 vs 207 (aa IPI) 155 VS 156 231 VS 241 68 None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx) 323 (ACVBP) 323 ACVBP vs 312 CHOP Feugier 2004 69 M 92 (CHOP-R) vs 107 (CHOP) 202 vs 197 161 vs 157 121 vs 120 61 vs 51 131 vs 132 24 NA no prophylaxis 202 R-CHOP Vs 197 CHOP Bernstein 2009 97/ 225 for CHOP were >60 yrs NR 899 aggressive lymphoma 191/ 225 CHOP 95/ 225 CHOP 81/225 CHOP 146/ 225 CHOP 20 years none for CHOP 121 IT MTX or radiation (24 Gy) 225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-B Boehme 2009 68 648 vs 569 1217 (944 DLBCL) 687 507 212 602 24 bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands. 475/1217 (IT-MTX) 608 RCHOP Vs 609 CHOP Kim 2012 59.5 NR 564 276 192 193 NR 10.5 ≥1 risk factor 59 IT RCHOP Kumar 2012 56 (prophylaxis) VS 58 (no prophylaxis) male: 74 vs 476 female: 43 vs 396 989 85 vs 454 55 vs 240 66 vs 220 57 vs 372 30 High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses 117/989 IT- 84/117 (AraC/MTX) S--33/117 (MTX) R-CHOP Holte 2013 54 97 vs 59 156 (145 DLBCL) 150 156 41 151 36 everyone 156/156 (S- Ara-c+ MTX) 1 dose of IT-MTX RCHOEP Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

BACKGROUND We evaluated mean QRS duration improvement immediately after cardiac resynchronization therapy (CRT) in patients with non-ischemic cardiomyopathy (NICM), with a left bundle branch block (LBBB) pattern on electrocardiogram (ECG), owing to obligatory right ventricular pacing or as a new finding; and to what extent. METHODS AND RESULTS We tabulated ECGs of 18 subjects, 24 hours before and after receiving CRT, for both groups. The percentage decreases of QRS duration in all groups were statistically similar (p