Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy

In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.KEYWORDS : Low Doses Fractionated Radiation Therapy (LDFRT), hyper-radiation sensitivity (HRS), induced radiation resistance (IRR), hyperfractionation, chemopotentiation, stereotactic body radiation therapy (SBRT), stereotactic ablative radiosurgery (SARS), stereotactic ablative radiotherapy (SABR), stereotactic radiosurgery (SRS), spatially fractionated GRID radiotherapy (SFGRT), lattice     

Genetic Variation of Echinococcus canadensis (G7) in Mexico

We evaluated the genetic variation of Echinococcus G7 strain in larval and adult stages using a fragment of the mitochondrial cox1 gen. Viscera of pigs, bovines, and sheep and fecal samples of dogs were inspected for cystic and canine echinococcosis, respectively; only pigs had hydatid cysts. Bayesian inferences grouped the sequences in an E. canadensis G7 cluster, suggesting that, in Mexico, this strain might be mainly present. Additionally, the population genetic and network analysis showed that E. canadensis in Mexico is very diverse and has probably been introduced several times from different sources. Finally, a scarce genetic differentiation between G6 (camel strain) and G7 (pig strain) populations was identified.Echinococcus granulosus sensu lato (s.l.) includes species that cause cystic echinococcosis (CE), one of the most important and widespread parasitic zoonoses. Recent phylogenetic studies based on both mitochondrial and nuclear DNA genes show that E. granulosus s.l. consists of at least four valid species: E. granulosus sensu stricto (s.s.; genotypes G1–G3), E. equinus (G4), E. ortleppi (G5), and E. canadensis (G6–G10). Genotypes G6/G7 are closely related and referred to as camel and pig strains, respectively.^1–3 The pig–dog cycle is mainly present in Mexico and maintains the G7 strain.^4,5 Although there are isolated reports of E. oligarthrus in a wild cat,⁶ E. ortleppi (E. granulosus s.l.; G5) in a patient,⁷ and E. granulosus s.s. (G1) in a rural pig, there is no evidence that these species are maintained in Mexico.⁸ No data of CE caused by G7 have been documented in Mexican patients, although there is a high number of E. canadensis G7-infected patients in central Europe, pointing to the importance of this strain as a cause of human CE.^9,10 There are only two genetic studies performed in samples from Mexico. Cruz-Reyes and others⁵ documented that G7 parasites of Mexican and Polish pig isolates showed similar patterns by restriction fragment length polymorphism (RFLP) of ribosomal DNA (rDNA) internal transcribed spacer 1 (ITS1) and random amplified polymorphic DNA (RAPD) techniques, and although polymerase chain reaction (PCR) -sequencing analysis of mitochondrial cox1 gen fragment was performed, no polymorphism data were reported. Sharma and others¹¹ identified two variants (A and B) inside of the G6/G7 group consisting of samples from Mexico and Argentina using five nuclear markers (elongation factor 1α, transforming growth factor-β receptor kinase, thioredoxin peroxidase, calreticulin, and ezrin-radixin-moesin-like protein). Because some local slaughter records from northern Mexico indicate the presence of Echinococcus spp. in livestock animals,⁵ the objective of this study was to investigate if parasites in pigs and dogs correspond to G7 and if so, describe its genetic variation.Infected animals were identified in the municipal slaughterhouse of Calera, Zacatecas (north central Mexico), where farm and backyard livestock animals coming from the whole state and other surrounding states were included. For this purpose, viscera from 387 pigs, 243 bovines, and 32 sheep were inspected for the larval stage of Echinococcus. Nine pigs (six pigs from Zacatecas, two pigs from Aguascalientes, and one pig from Morelos) were found infected, and hydatid cysts were obtained under aseptic conditions. After cyst contents were aspirated and centrifuged, aliquots were examined under microscopy to confirm the presence of protoscolices, and pellets were kept in 70% ethanol at −20°C until DNA extraction. Each cyst from each animal was considered as an isolate.Based on the presence of the parasites previously identified in Calera''s slaughterhouse, a rural community located in the central area of Zacatecas at 22°55′ N, 102°48′ W was selected to look for the adult stage of this parasite. For this search, all dogs (60) present in the community were sampled one time for feces after obtaining verbal consent from the owner; samples were used to identify taeniid eggs by the Faust technique, antigens in stool samples (copro-antigens) by enzyme-linked immunosorbent assay (ELISA; CpAg ELISA), and DNA by Copro-PCR. The CpAg ELISA was performed as described by Allan and others¹² and Moro and others.¹³ For Copro-PCR, only positive samples by CpAg ELISA were analyzed using JB3 and JB4 primers to amplify a cox1 gen fragment.¹⁴ Coprological analysis of dogs showed that 11 samples were positive by CpAg ELISA (18.3%); only 2 of these samples had taeniid tapeworms (3.4%), and 3 of 11 samples yielded products of approximately 450 bp. All amplicons obtained of hydatid cysts and fecal samples were purified, sequenced on both strands, submitted to GenBank (accession numbers {"type":"entrez-nucleotide-range","attrs":{"text":"KF734649-KF734660","start_term":"KF734649","end_term":"KF734660","start_term_id":"570963772","end_term_id":"570963794"}}KF734649-KF734660), and compared with several mitochondrial DNA sequences of cox1. Dogs positive for taeniid eggs or antigens were purged and treated with praziquantel at 30 mg/kg and arecoline bromide at 2 mg/kg. The protocol was previously approved by the Ethics and Research Committees of the General Hospital “Dr. Manuel Gea Gonzalez”; government and health authorities of the municipality and community also authorized our study.All sequences were subjected to the Basic Local Alignment Search Tool (BLAST) search in the GenBank database; multiple alignments were performed with the CLUSTAL W and MUSCLE programs,^15,16 with manual adjusted in MEGA program v5¹⁷ to determine the appropriate model of molecular evolution in the Modeltest 3.7 program.¹⁸ The phylogenetic reconstruction using Bayesian inference was performed with Mr Bayes 3.2.1 program.¹⁹ Unrooted haplotype networks were created using NETWORK 4.611 software and nested according to the rules in median-joining networks.²⁰ An analysis of genetic diversity within and between populations was performed using DnaSPv4²¹ and included nucleotide diversity (π), haplotype polymorphism (θ), genetic differentiation index (F_ST), and Tajima''s D test. Analysis of molecular variance (AMOVA) was used to examine the population genetic structure between populations by Φ_ST as the genetic fixation index (analogous to F_ST) obtained by ARLEQUIN software.²²After multiple alignments, all sequences of larval and adult stages showed 98% or higher identity with E. canadensis, whereas the Bayesian phylogenetic tree and the haplotype network inference grouped these sequences in the E. canadensis G7 cluster. Sequences for cox1 of E. canadensis from Africa, Asia, Europe, Latin America, and North America deposited in the GenBank databases (N = 58) as well as our sequences (accession numbers {"type":"entrez-nucleotide-range","attrs":{"text":"KF734649-KF734660","start_term":"KF734649","end_term":"KF734660","start_term_id":"570963772","end_term_id":"570963794"}}KF734649-KF734660) were analyzed. The results for π and θ were 0.0118 and 0.718, and the result of Tajima''s D test was −2.1885 (P < 0.01). Genetic differentiation indexes between different paired sequences of E. canadensis genotypes are shown in

Cenani–Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation

Cenani–Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype–phenotype correlations in CLS and support kidney anomalies as a frequent associated feature.     

A case report of cecal plasmablastic lymphoma in a HIV-negative patient

Plasmablastic lymphoma (PBL) is a unique type of diffuse proliferation of large neoplastic lymphoid cells most of which resemble B immunoblasts, but all tumor cells show the immunophenotype of plasma cells. It has a strong predilection for jaw and oral cavity in HIV-positive patients. Incidences of extraoral location of this tumor is increasingly being recognized especially in HIV-negative patients for example, stomach, jejunum, omentum, anorectum, lungs, testes, soft tissues, lymph nodes, bone marrow, skin, and central nervous system. We present a case of PBL found in cecum in an HIV-negative patient. It was accompanied by lung and lymph node involvement and presented as abdominal mass. This is only the second reported case of PBL originating in cecum.     

Cross-sectional assessment of prevalence and correlates of blood-borne and sexually-transmitted infections among Afghan National Army recruits

ABSTRACT: BACKGROUND: Few data are available in Afghanistan to shape national military force health practices, particularly with regard to sexually-transmitted infections (STIs). We measured prevalence and correlates of HIV, syphilis, herpes simplex 2 virus (HSV-2), and hepatitis C virus (HCV) among Afghan National Army (ANA) recruits. METHODS: A cross-sectional sample of male ANA recruits aged 18--35 years were randomly selected at the Kabul Military Training Center between February 2010 and January 2011. Participants completed an interviewer-administered questionnaire and serum-based rapid testing for syphilis, hepatitis C virus antibody on-site; HIV and HSV-2 screening, and confirmatory testing were performed off-site. Prevalence of each infection was calculated and logistic regression analysis performed to identify correlates. RESULTS: Of 5313 recruits approached, 4750 consented to participation. Participants had a mean age of 21.8 years (SD[PLUS-MINUS SIGN]3.8), 65.5% had lived outside Afghanistan, and 44.3% had no formal education. Few reported prior marijuana (16.3%), alcohol (5.3%), or opium (3.4%) use. Of sexually active recruits (58.7%, N = 2786), 21.3% reported paying women for sex and 21.3% reported sex with males. Prevalence of HIV (0.063%, 95% CI: 0.013- 0.19), syphilis (0.65%, 95% CI: 0.44 -- 0.93), and HCV (0.82%, 95% CI: 0.58 -- 1.12) were quite low. Prevalence of HSV-2 was 3.03% (95% CI: 2.56 - 3.57), which was independently associated with age (Adjusted Odds Ratio (AOR) = 1.04, 95% CI: 1.00 - 1.09) and having a television (socioeconomic marker) (AOR = 1.46, 95% CI: 1.03 -- 2.05). CONCLUSION: Though prevalence of HIV, HCV, syphilis, and HSV-2 was low, sexual risk behaviors and intoxicant use were present among a substantial minority, indicating need for prevention programming. Formative work is needed to determine a culturally appropriate approach for prevention programming to reduce STI risk among Afghan National Army troops.     

Development of hydrophobic reduced graphene oxide as a new efficient approach for photochemotherapy

Nowadays, chemotherapy is one of the crucial and common therapies in the world. So far, it has been revealed to be highly promising, yet patients suffer from the consequences of severe negative medical dosages. In order to overcome these issues, the enhancement of photothermal chemotherapy with reduced graphene oxide (rGO) as a photothermal agent (PTA) is widely utilised in current medical technologies. This is due to its high near-infrared region (NIR) response, in vitro or in vivo organism biocompatibility, low risk of side effects, and effective positive results. Moreover, rGO not only has the ability to ensure that selective cancer cells have a higher mortality rate but can also improve the growth rate of recovering tissues that are untouched by necrosis and apoptosis. These two pathways are specific diverse modalities of cell death that are distinguished by cell membrane disruption and deoxyribonucleic acid (DNA) disintegration of the membrane via phosphatidylserine exposure in the absence of cell membrane damage. Therefore, this review aimed to demonstrate the recent achievements in the modification of rGO nanoparticles as a PTA as well as present a new approach for performing photochemotherapy in the clinical setting.

rGO of QD-rGO nanocomposite could absorb and convert into heat when harvested under NIR radiation, resulting cell death with reduction of fluorescence.