Journal articles on the topic 'Phage therapy investigation'
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Johnson, R. P., C. L. Gyles, W. E. Huff, S. Ojha, G. R. Huff, N. C. Rath, and A. M. Donoghue. "Bacteriophages for prophylaxis and therapy in cattle, poultry and pigs." Animal Health Research Reviews 9, no. 2 (December 2008): 201–15. http://dx.doi.org/10.1017/s1466252308001576.
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AbstractThe successful use of virulent (lytic) bacteriophages (phages) in preventing and treating neonatal enterotoxigenicEscherichia coliinfections in calves, lambs and pigs has prompted investigation of other applications of phage therapy in food animals. While results have been very variable, some indicate that phage therapy is potentially useful in virulentSalmonellaandE. coliinfections in chickens, calves and pigs, and in control of the food-borne pathogensSalmonellaandCampylobacter jejuniin chickens andE. coliO157:H7 in cattle. However, more rigorous and comprehensive research is required to determine the true potential of phage therapy. Particular challenges include the selection and characterization of phages, practical modes of administration, and development of formulations that maintain the viability of phages for administration. Also, meaningful evaluation of phage therapy will require animal studies that closely represent the intended use, and will include thorough investigation of the emergence and characteristics of phage resistant bacteria. As well, effective use will require understanding the ecology and dynamics of the endemic and therapeutic phages and their interactions with target bacteria in the farm environment. In the event that the potential of phage therapy is realized, adoption will depend on its efficacy and complementarity relative to other interventions. Another potential challenge will be regulatory approval.
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O'Connell, Larry, Ondrej Mandula, Loïc Leroy, Axelle Aubert, Pierre R. Marcoux, and Yoann Roupioz. "Ultrafast and Multiplexed Bacteriophage Susceptibility Testing by Surface Plasmon Resonance and Phase Imaging of Immobilized Phage Microarrays." Chemosensors 10, no. 5 (May 19, 2022): 192. http://dx.doi.org/10.3390/chemosensors10050192.
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In the context of bacteriophage (phage) therapy, there is an urgent need for a method permitting multiplexed, parallel phage susceptibility testing (PST) prior to the formulation of personalized phage cocktails for administration to patients suffering from antimicrobial-resistant bacterial infections. Methods based on surface plasmon resonance imaging (SPRi) and phase imaging were demonstrated as candidates for very rapid (<2 h) PST in the broth phase. Biosensing layers composed of arrays of phages 44AHJD, P68, and gh-1 were covalently immobilized on the surface of an SPRi prism and exposed to liquid culture of either Pseudomonas putida or methicillin-resistant Staphylococcus aureus (i.e., either the phages’ host or non-host bacteria). Monitoring of reflectivity reveals susceptibility of the challenge bacteria to the immobilized phage strains. Investigation of phase imaging of lytic replication of gh-1 demonstrates PST at the single-cell scale, without requiring phage immobilization. SPRi sensorgrams show that on-target regions increase in reflectivity more slowly, stabilizing later and to a lower level compared to off-target regions. Phage susceptibility can be revealed in as little as 30 min in both the SPRi and phase imaging methods.
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Bochkareva, Svetlana Sergeevna, A. V. Karaulov, A. V. Aleshkin, I. I. Novikova, I. M. Fedorova, M. S. Blayaher, S. I. Koteleva, and I. V. Kapustin. "APPROACHES TO THE ESTIMATION OF SOME PARAMETERS OF HUMORAL AND CELLULAR IMMUNE RESPONSE TO BACTERIOPHAGES." Russian Clinical Laboratory Diagnostics 64, no. 4 (October 7, 2019): 237–42. http://dx.doi.org/10.18821/0869-2084-2019-64-4-237-242.
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The aim of the study was to develop some approaches to evaluate the basic parameters of the humoral and cellular immune response to a bacteriophage, taking into account the multifactorial aspects of its interaction with both the pathogen and the macroorganism. The necessary reagents were obtained and a line of diagnostic ELISA test systems was designed to allow semi-quantitative assessment of the anti-bacteriophage IgG-antibody level in serum or other biological human fluids, as well as in preparations obtained from human blood. The need for neutralization reaction to determine the effect of detected antibodies on phage activity against a target bacterium has been proven. Testing the approaches used in the investigation of patients’ blood sera showed that antibodies to bacteriophages synthesized during phage therapy are not always neutralizing. Also approaches have been developed to evaluate cell immunity reactions to bacteriophage namely to identify T-lymphocytes (T-helpers and cytotoxic lymphocytes) that can be activated in the presence of the phage under study (by expressing the early activation marker (CD69) and by the ability to produce IFNγ). Approbation of the technique in the study of lymphocytes in patients during phage therapy showed the presence of activated cells by both the CD69 expression and IFNγ production, the dynamics of which depended on the timing and frequency of therapy. The appearance of neutralizing anti-phage antibodies and corresponding activated T-lymphocytes should be taken into account in phage therapy, the effectiveness of which can directly depend not only on the activity of the phage against the target bacterium, but also on the response of the patient’s immune system to the bacteriophage.
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Pu, Mingfang, Pengjun Han, Guangye Zhang, Yucong Liu, Yahao Li, Fei Li, Mengzhe Li, et al. "Characterization and Comparative Genomics Analysis of a New Bacteriophage BUCT610 against Klebsiella pneumoniae and Efficacy Assessment in Galleria mellonella Larvae." International Journal of Molecular Sciences 23, no. 14 (July 21, 2022): 8040. http://dx.doi.org/10.3390/ijms23148040.
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The spread of multidrug-resistant Klebsiella pneumoniae (MDR-KP) has become an emerging threat as a result of the overuse of antibiotics. Bacteriophage (phage) therapy is considered to be a promising alternative treatment for MDR-KP infection compared with antibiotic therapy. In this research, a lytic phage BUCT610 was isolated from hospital sewage. The assembled genome of BUCT610 was 46,774 bp in length, with a GC content of 48%. A total of 83 open reading frames (ORFs) and no virulence or antimicrobial resistance genes were annotated in the BUCT610 genome. Comparative genomics and phylogenetic analyses showed that BUCT610 was most closely linked with the Vibrio phage pYD38-A and shared 69% homology. In addition, bacteriophage BUCT610 exhibited excellent thermal stability (4–75 °C) and broad pH tolerance (pH 3–12) in the stability test. In vivo investigation results showed that BUCT610 significantly increased the survival rate of Klebsiella pneumonia-infected Galleria mellonella larvae from 13.33% to 83.33% within 72 h. In conclusion, these findings indicate that phage BUCT610 holds great promise as an alternative agent with excellent stability for the treatment of MDR-KP infection.
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Jain, Rishi, Andrea L. Knorr, Joseph Bernacki, and Ranjan Srivastava. "Investigation of Bacteriophage MS2 Viral Dynamics Using Model Discrimination Analysis and the Implications for Phage Therapy." Biotechnology Progress 22, no. 6 (2006): 1650–58. http://dx.doi.org/10.1002/bp060161s.
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Titze, Isabel, Tatiana Lehnherr, Hansjörg Lehnherr, and Volker Krömker. "Efficacy of Bacteriophages Against Staphylococcus aureus Isolates from Bovine Mastitis." Pharmaceuticals 13, no. 3 (February 26, 2020): 35. http://dx.doi.org/10.3390/ph13030035.
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The lytic efficacy of bacteriophages against Staphylococcus aureus isolates from bovine milk was investigated in vitro, regarding possible applications in the therapy of udder inflammation caused by bacterial infections (mastitis). The host range of sequenced, lytic bacteriophages was determined against a collection of 92 Staphylococcus (S.) aureus isolates. The isolates originated from quarter foremilk samples of clinical and subclinical mastitis cases. A spot test and a subsequent plaque assay were used to determine the phage host range. According to their host range, propagation and storage properties, three phages, STA1.ST29, EB1.ST11, and EB1.ST27, were selected for preparing a bacteriophage mixture (1:1:1), which was examined for its lytic activity against S. aureus in pasteurized and raw milk. It was found that almost two thirds of the isolates could be lysed by at least one of the tested phages. The bacteriophage mixture was able to reduce the S. aureus germ density in pasteurized milk and its reduction ability was maintained in raw milk, with only a moderate decrease compared to the results in pasteurized milk. The significant reduction ability of the phage mixture in raw milk promotes further in vivo investigation.
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Quaranta, Gianluca, Alessandra Guarnaccia, Giovanni Fancello, Chiara Agrillo, Federica Iannarelli, Maurizio Sanguinetti, and Luca Masucci. "Fecal Microbiota Transplantation and Other Gut Microbiota Manipulation Strategies." Microorganisms 10, no. 12 (December 7, 2022): 2424. http://dx.doi.org/10.3390/microorganisms10122424.
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The gut microbiota is composed of bacteria, archaea, phages, and protozoa. It is now well known that their mutual interactions and metabolism influence host organism pathophysiology. Over the years, there has been growing interest in the composition of the gut microbiota and intervention strategies in order to modulate it. Characterizing the gut microbial populations represents the first step to clarifying the impact on the health/illness equilibrium, and then developing potential tools suited for each clinical disorder. In this review, we discuss the current gut microbiota manipulation strategies available and their clinical applications in personalized medicine. Among them, FMT represents the most widely explored therapeutic tools as recent guidelines and standardization protocols, not only for intestinal disorders. On the other hand, the use of prebiotics and probiotics has evidence of encouraging findings on their safety, patient compliance, and inter-individual effectiveness. In recent years, avant-garde approaches have emerged, including engineered bacterial strains, phage therapy, and genome editing (CRISPR-Cas9), which require further investigation through clinical trials.
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Liu, Yanxi, Mengjiao Liu, Ran Hu, Jun Bai, Xiaoqing He, and Yi Jin. "Isolation of the Novel Phage PHB09 and Its Potential Use against the Plant Pathogen Pseudomonas syringae pv. actinidiae." Viruses 13, no. 11 (November 14, 2021): 2275. http://dx.doi.org/10.3390/v13112275.
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Bacteriophages are viruses that specifically infect target bacteria. Recently, bacteriophages have been considered potential biological control agents for bacterial pathogens due to their host specificity. Pseudomonas syringae pv. actinidiae (Psa) is a reemerging pathogen that causes bacterial canker of kiwifruit (Actinidia sp.). The economic impact of this pest and the development of resistance to antibiotics and copper sprays in Psa and other pathovars have led to investigation of alternative management strategies. Phage therapy may be a useful alternative to conventional treatments for controlling Psa infections. Although the efficacy of bacteriophage φ6 was evaluated for the control of Psa, the characteristics of other DNA bacteriophages infecting Psa remain unclear. In this study, the PHB09 lytic bacteriophage specific to Psa was isolated from kiwifruit orchard soil. Extensive host range testing using Psa isolated from kiwifruit orchards and other Pseudomonas strains showed PHB09 has a narrow host range. It remained stable over a wide range of temperatures (4–50 °C) and pH values (pH 3–11) and maintained stability for 50 min under ultraviolet irradiation. Complete genome sequence analysis indicated PHB09 might belong to a new myovirus genus in Caudoviricetes. Its genome contains a total of 94,844 bp and 186 predicted genes associated with phage structure, packaging, host lysis, DNA manipulation, transcription, and additional functions. The isolation and identification of PHB09 enrich the research on Pseudomonas phages and provide a promising biocontrol agent against kiwifruit bacterial canker.
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Bitounis, Dimitrios, Raphaelle Fanciullino, Athanassios Iliadis, and Joseph Ciccolini. "Optimizing Druggability through Liposomal Formulations: New Approaches to an Old Concept." ISRN Pharmaceutics 2012 (February 9, 2012): 1–11. http://dx.doi.org/10.5402/2012/738432.
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Developing innovative delivery strategies remains an ongoing task to improve both efficacy and safety of drug-based therapy. Nanomedicine is now a promising field of investigation, rising high expectancies for treating various diseases such as malignancies. Putting drugs into liposome is an old story that started in the late 1960s. Because of the near-total biocompatibility of their lipidic bilayer, liposomes are less concerned with the safety issue related to the possible long-term accumulation in the body of most nanoobjects currently developed in nanomedicine. Additionally, novel techniques and recent efforts to achieve better stability (e.g., through sheddable coating), combined with a higher selectivity towards target cells (e.g., by anchoring monoclonal antibodies or incorporating phage fusion protein), make new liposomal drugs an attractive and challenging opportunity to improve clinical outcome in a variety of disease. This review covers the physicochemistry of liposomes and the recent technical improvements in the preparation of liposome-encapsulated drugs in regard to the scientific and medical stakes.
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Larché, Jérôme, Flavie Pouillot, Christiane Essoh, Balázs Libisch, Monica Straut, Je Chul Lee, Charles Soler, et al. "Rapid Identification of International Multidrug-Resistant Pseudomonas aeruginosa Clones by Multiple-Locus Variable Number of Tandem Repeats Analysis and Investigation of Their Susceptibility to Lytic Bacteriophages." Antimicrobial Agents and Chemotherapy 56, no. 12 (September 17, 2012): 6175–80. http://dx.doi.org/10.1128/aac.01233-12.
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ABSTRACTThe objective of this study was to determine the genetic diversity of multidrug-resistant (MDR)Pseudomonas aeruginosastrains isolated over a period of 12 months in two French hospitals and to test their susceptibility to bacteriophages. A total of 47 MDR isolates recovered from hospitalized patients were genotyped using multiple-locus variable number of tandem repeats analysis. The genotypes were distributed into five clones (including 19, 5, 5, 3, and 3 isolates, respectively) and 12 singletons. Comparison to 77 MDR strains from three other countries, and MLST analysis of selected isolates showed the predominance of international MDR clones. The larger clone, CC235, contained 59 isolates displaying different antibiotic resistance mechanisms, including the presence of the GES1, VIM-2, VIM-4, and IMP-1 β-lactamases. Three newly isolatedP. aeruginosabacteriophages were found to lyse 42 of the 44 analyzed strains, distributed into the different clonal complexes. This pilot study suggests that systematic genotyping ofP. aeruginosaMDR strains could improve our epidemiological understanding of transmission at both the local (hospital) and the national level and that phage therapy could be an alternative or a complementary treatment to antibiotics for treating MDR-infected patients.
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Silva, Gabriela, Joana Sales-Dias, Diogo Casal, Sara Alves, Giacomo Domenici, Clara Barreto, Carolina Matos, et al. "Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer." Cancers 13, no. 16 (August 13, 2021): 4074. http://dx.doi.org/10.3390/cancers13164074.
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The Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER+) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER+ BC; however, relapse is a major clinical issue, and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment, which was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibited DLL1 specificity and affinity in the low nanomolar range and significantly impaired DLL1-Notch signaling and expression of Notch target genes in ER+ BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. These findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER+ BC, warranting further preclinical investigation.
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Brettschneider, Kerstin, Anja Naumann, Sonja Neimanis, Joerg Kahle, Christine Heller, Thomas Klingebiel, Dirk Schwabe, and Christoph Koenigs. "Functional Analysis of Phage Display Selected Single-Chain Variable Antibody Fragments (scFvs) Specific for Anti-FVIII Antibodies." Blood 124, no. 21 (December 6, 2014): 1499. http://dx.doi.org/10.1182/blood.v124.21.1499.1499.
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Abstract The development of inhibitory antibodies against coagulation factor VIII (FVIII) is currently the most serious complication for hemophilia A patients that undergo FVIII replacement therapy. In addition, non-hemophilia A patients can spontaneously develop inhibitory auto-antibodies to FVIII, which results in acquired haemophilia A. The control of the allo- or autoimmune response to FVIII apparently includes the elicitation of anti-idiotypic antibodies. In this study the capacity of anti-idiotypic single-chain variable antibody fragments (scFvs) for neutralization of inhibitory anti-FVIII antibodies (FVIII inhibitors) was evaluated in vitro and in vivo. Anti-idiotypic scFvs were selected from phage-displayed libraries against murine monoclonal FVIII-specific inhibitors. As the majority of inhibitory antibodies is directed against the A2 or C2 domain of FVIII, strongly inhibitory A2- and C2-specific antibodies served as targets. Selected scFvs were expressed as scFv-Fc fusion proteins. Analysis of the scFv-Fcs by ELISA confirmed the specific binding to the cognate targets and binding studies via surface plasmon resonance revealed high affinities within the nanomolar range. Further characterization showed that binding of inhibitors to immobilized FVIII was blocked by specific scFv-Fcs in vitro. The ability of scFv-Fcs to neutralize their corresponding inhibitors was analyzed in a functional clotting assay. By adding scFv-Fcs to plasma spiked with inhibitors, FVIII activity was restored to 80% in a concentration dependent manner. FVIII knockout mice served as model organism for testing the capacity of scFv-Fcs to restore coagulation in vivo. Subsequent injection of FVIII following the injection of the inhibitors resulted in a largely reduced FVIII activity. However, FVIII activity was recovered in a concentration dependent manner by adding cognate anti-idiotypes. The scFv-Fcs were either preincubated with the corresponding inhibitor or added to the FVIII mixture without preincubation. The latter represents an adaption to a therapeutic setting. In conclusion, phage display selected anti-idiotypic scFvs are able to bind and effectively neutralize their target inhibitors in vitro and in vivo. Based on these promising results the potential of anti-idiotypic scFvs for the development of specific cell based immunotherapies for hemophilia A patients with inhibitors is currently under investigation. Disclosures No relevant conflicts of interest to declare.
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Luz, Daniela, Fernando D. Gómez, Raíssa L. Ferreira, Bruna S. Melo, Beatriz E. C. Guth, Wagner Quintilio, Ana Maria Moro, et al. "The Deleterious Effects of Shiga Toxin Type 2 Are Neutralized In Vitro by FabF8:Stx2 Recombinant Monoclonal Antibody." Toxins 13, no. 11 (November 22, 2021): 825. http://dx.doi.org/10.3390/toxins13110825.
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Hemolytic Uremic Syndrome (HUS) associated with Shiga-toxigenic Escherichia coli (STEC) infections is the principal cause of acute renal injury in pediatric age groups. Shiga toxin type 2 (Stx2) has in vitro cytotoxic effects on kidney cells, including human glomerular endothelial (HGEC) and Vero cells. Neither a licensed vaccine nor effective therapy for HUS is available for humans. Recombinant antibodies against Stx2, produced in bacteria, appeared as the utmost tool to prevent HUS. Therefore, in this work, a recombinant FabF8:Stx2 was selected from a human Fab antibody library by phage display, characterized, and analyzed for its ability to neutralize the Stx activity from different STEC-Stx2 and Stx1/Stx2 producing strains in a gold standard Vero cell assay, and the Stx2 cytotoxic effects on primary cultures of HGEC. This recombinant Fab showed a dissociation constant of 13.8 nM and a half maximum effective concentration (EC50) of 160 ng/mL to Stx2. Additionally, FabF8:Stx2 neutralized, in different percentages, the cytotoxic effects of Stx2 and Stx1/2 from different STEC strains on Vero cells. Moreover, it significantly prevented the deleterious effects of Stx2 in a dose-dependent manner (up to 83%) in HGEC and protected this cell up to 90% from apoptosis and necrosis. Therefore, this novel and simple anti-Stx2 biomolecule will allow further investigation as a new therapeutic option that could improve STEC and HUS patient outcomes.
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Apte, Suneel S. "Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis." Biochemical Journal 473, no. 1 (December 9, 2015): e1-e4. http://dx.doi.org/10.1042/bj20151072.
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The extracellular matrix of articular cartilage is structurally specialized for efficient absorption of mechanical impact. In particular, giant aggregates of the large chondroitin sulfate proteoglycan, aggrecan, with the glycosaminoglycan, hyaluronan, allow cartilage to resist compressive load. Proteolysis of aggrecan by members of the proteinase family ADAMTS (A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif), was identified as an early step in the inexorable destruction of cartilage in osteoarthritis (OA). Of the investigated proteinases, ADAMTS5 has emerged as a principal mediator of aggrecan loss in OA, convincingly so in mouse models, and with high probability in humans. ADAMTS5 has a bipartite organization, comprising a proteinase domain and an ancillary domain containing exosites for interaction with aggrecan and other substrates. In a recent issue of this journal, Santamaria et al. characterized anti-ADAMTS5 monoclonal antibodies isolated from a phage display library. By blocking the catalytic site of the ADAMTS5 immunogen with a synthetic inhibitor, the authors of the paper biased selection of antibodies to the ancillary domain. This work, together with other antibodies targeting ADAMTS5, offers diverse, high-affinity and, as far as can be determined, selective aggrecanase inhibitors. Mapping of their epitopes provided novel insights into ADAMTS5 interactions with aggrecan. These monoclonal antibodies deserve continued investigation for potential arthritis therapy, although their successful use will require a comprehensive understanding of the physiological roles of ADAMTS5, and its regulation, intrinsic properties and intermolecular interactions.
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Jenkins, Timothy, Thomas Fryer, Rasmus Dehli, Jonas Jürgensen, Albert Fuglsang-Madsen, Sofie Føns, and Andreas Laustsen. "Toxin Neutralization Using Alternative Binding Proteins." Toxins 11, no. 1 (January 17, 2019): 53. http://dx.doi.org/10.3390/toxins11010053.
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Animal toxins present a major threat to human health worldwide, predominantly through snakebite envenomings, which are responsible for over 100,000 deaths each year. To date, the only available treatment against snakebite envenoming is plasma-derived antivenom. However, despite being key to limiting morbidity and mortality among snakebite victims, current antivenoms suffer from several drawbacks, such as immunogenicity and high cost of production. Consequently, avenues for improving envenoming therapy, such as the discovery of toxin-sequestering monoclonal antibodies against medically important target toxins through phage display selection, are being explored. However, alternative binding protein scaffolds that exhibit certain advantages compared to the well-known immunoglobulin G scaffold, including high stability under harsh conditions and low cost of production, may pose as possible low-cost alternatives to antibody-based therapeutics. There is now a plethora of alternative binding protein scaffolds, ranging from antibody derivatives (e.g., nanobodies), through rationally designed derivatives of other human proteins (e.g., DARPins), to derivatives of non-human proteins (e.g., affibodies), all exhibiting different biochemical and pharmacokinetic profiles. Undeniably, the high level of engineerability and potentially low cost of production, associated with many alternative protein scaffolds, present an exciting possibility for the future of snakebite therapeutics and merit thorough investigation. In this review, a comprehensive overview of the different types of binding protein scaffolds is provided together with a discussion on their relevance as potential modalities for use as next-generation antivenoms.
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Nakazaki, Yukoh, Takao Hashiguchi, Fuyumi Takano, Ryo Kurita, Shirley Clift, Dale G. Ando, Shigetaka Asano, and Kenzaburo Tani. "Analysis and Identification of Serological Tumor Antigens in Patients Treated with the GM-CSF-Gene Transduced-Autologous Tumor Vaccines (GVAX®) for Renal Cell Carcinoma." Blood 104, no. 11 (November 16, 2004): 5279. http://dx.doi.org/10.1182/blood.v104.11.5279.5279.
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Abstract Vaccination of GM-CSF-transduced tumor cells (GVAX®) has been demonstrated to induce cellular and humoral immune response to tumors in animal studies as well as human clinical trials. We have recently done clinical trials of GVAX® using autologous renal cell cancer (RCC) cells. Four patients with advanced RCC, who were entered to our clinical gene therapy trial, received multiple GVAX® injections every two weeks. Two out of four patients, Cases 2 and 4, are long term survivors living more than 62 and 42 months, respectively, after the start of vaccination. To examine whether the therapeutic regimen induced antitumor antibody responses in them, we compared the serum antibody reactivity against autologous tumor cell lysates before and after the vaccinations by immunoblot analysis. Using post-therapy serum as probes, proteins of around 250 kDa and 60 kDa generated clear signals, whereas the pre-vaccination serum showed no or only weak signals at the same position, suggesting that the gene therapy induced an antibody response in them. In three of them (Cases 2–4), the induction of antibodies immunoreactive with these two proteins was significant, while the results were less clear in Case 1. The suspected common antigen was actually demonstrated in both RCC lysates and normal renal cell lysates, and in human lip-derived fibroblasts, but not in H69 lung cancer cells. The strongest signal was observed in Case 2 serum obtained at 67 days after the initial vaccination, between the 5th and 6th vaccinations. This response was maintained from day 67 until day 281, just after the 17th vaccination, although it decreased slightly. After the last vaccination, the immunoreactivity remained at a lower level, although it did not disappear completely. Based on the above results, we applied SEREX, the serological identification of antigens by recombinant expression cloning, using patient’s serum, to isolate the serological RCC tumor antigen genes. We constructed RCC cDNA-expression libraries on lambda phage vector, and screened the plaques with Case 2 serum pooled between days 25 and 80 after the first vaccination. The mRNA source was Case 2 RCC or VMRC-RCW RCC cell line. From above libraries, totally two million recombinant phages screened, twenty-eight SEREX positive clones, which passed secondary or further screening, were isolated. Sequencing analysis revealed the clones were composed of thirteen independent gene products, some of them have not been reported as SEREX defined antigen in previous studies. Expression profiling experiment showed, one of the newly defined SEREX antigen, testicular nuclear autoantigenic sperm protein (tNASP) gene expression had tendency to be dominantly expressed in tumor tissue compared with corresponding normal tissue. To precisely determine the serum antibody titre against the isolated SEREX defined antigens, we constructed the recombinant antigen/epitope tag expression vector and expressed in E. coli. The antibody titration in cancer patients or healty donor against these antigens using obtained recombinant antigen protein has been under investigation. The identification of the new anti-RCC antigen might cast a new light on the treatment of patients suffered from advanced RCC.
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Klausz, Katja, Renate Burger, Christian Kellner, Andreas Guenther, Matthias Peipp, and Martin Gramatzki. "The Novel ADCC-Optimized Human CD54 (ICAM-1) Antibody MSH-TP15e Has Potent Anti-Myeloma Activity." Blood 128, no. 22 (December 2, 2016): 4471. http://dx.doi.org/10.1182/blood.v128.22.4471.4471.
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Abstract Background: Monoclonal antibodies directed against various target antigens have proven efficacy in cancer therapy including hematological malignancies. Recently, daratumumab and elotuzumab became the first antibodies approved for the treatment of multiple myeloma (MM). Due to the substantial number of patients still in need for long-term disease control, the investigation of additional target structures and potent molecule formats for antibody-based therapy of MM remains important. Methods: Human synthetic single-chain fragment variable (scFv) phage display libraries were subjected to a cellular screening approach. The MSH-TP15 clone was selected based on its binding to various MM cell lines and patient-derived CD138-positive malignant plasma cells. Intercellular adhesion molecule-1 (ICAM-1/CD54), known to be important for the interaction of malignant plasma cells with the bone marrow microenvironment, was identified as target antigen. Based on the scFv sequence, fully human IgG1 antibody variants with selected mutations in the Fc domain were constructed to generate wild-type, antibody-dependent cell-mediated cytotoxicity (ADCC)-optimized and Fc-knockout variants. First, these variants were analyzed for their capacity to kill MM cells in vitro. Apoptosis induction and growth inhibition were tested by flow cytometry and in MTS proliferation assays. ADCC and complement-dependent cytotoxicity were investigated in chromium-release assays using human serum, peripheral blood mononuclear cells or purified NK cells of healthy donors. In vivoefficacy of an ADCC-optimized variant was analyzed in the INA-6 myeloma xenograft model. Results: The MSH-TP15 antibodies target an epitope on the N-terminal part of the extracellular domain of human ICAM-1/CD54. The antibody variants showed no anti-proliferative effects on patient-derived bone marrow stromal cells, nor directly induced apoptosis or inhibited proliferation of myeloma cells. While complement-dependent cytotoxic activity was generally absent, the Fc-engineered antibody variant MSH-TP15e significantly triggered ADCC against various MM cell lines and freshly isolated patient myeloma cells. The recruitment of human NK cells was crucial for the cytotoxic effects observed in vitro. Importantly, an ADCC-optimized variant completely prevented tumor engraftment in the INA-6 xenograft model. Conclusions: The novel ADCC-optimized fully human antibody MSH-TP15e directed against ICAM-1/CD54 exerts potent anti-myeloma activity in vitro and in vivo. Therefore, it has promising characteristics and will be further evaluated for MM immunotherapy. Disclosures Guenther: Novartis: Consultancy, Honoraria; Celgene: Honoraria; Takeda: Consultancy, Honoraria.
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Mizuno, Carolina M., Tiffany Luong, Robert Cederstrom, Mart Krupovic, Laurent Debarbieux, and Dwayne R. Roach. "Isolation and Characterization of Bacteriophages That Infect Citrobacter rodentium, a Model Pathogen for Intestinal Diseases." Viruses 12, no. 7 (July 8, 2020): 737. http://dx.doi.org/10.3390/v12070737.
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Enteropathogenic Escherichia coli (EPEC) is a major pathogen for diarrheal diseases among children. Antibiotics, when used appropriately, are effective; however, their overuse and misuse have led to the rise of antibiotic resistance worldwide. Thus, there are renewed efforts into the development of phage therapy as an alternative antibacterial therapy. Because EPEC in vivo models have shortcomings, a surrogate is used to study the mouse pathogen Citrobacter rodentium in animal models. In this study, two new phages CrRp3 and CrRp10, which infect C. rodentium, were isolated and characterized. CrRp3 was found to be a new species within the genus Vectrevirus, and CrRp10 is a new strain within the species Escherichia virus Ime09, in the genus Tequatrovirus. Both phages appear to have independently evolved from E. coli phages, rather than other Citrobacter spp. phages. Neither phage strain carries known genes associated with bacterial virulence, antibiotic resistance, or lysogeny. CrRp3 is more potent, having a 24-fold faster adsorption rate and shorter lytic cycle when compared to the same properties of CrRp10. However, a lysis curve analysis revealed that CrRp10 prevented growth of C. rodentium for 18 h, whereas resistance developed against CrRp3 within 9 h. We also show that hypoxic (5% oxygen) conditions decreased CrRp3 ability to control bacterial densities in culture. In contrast, low oxygen conditions did not affect CrRp10 ability to replicate on C. rodentium. Together, CrRp10 is likely to be the better candidate for future phage therapy investigations.
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Loponte, Rosa, Ugo Pagnini, Giuseppe Iovane, and Giuseppe Pisanelli. "Phage Therapy in Veterinary Medicine." Antibiotics 10, no. 4 (April 11, 2021): 421. http://dx.doi.org/10.3390/antibiotics10040421.
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To overcome the obstacle of antimicrobial resistance, researchers are investigating the use of phage therapy as an alternative and/or supplementation to antibiotics to treat and prevent infections both in humans and in animals. In the first part of this review, we describe the unique biological characteristics of bacteriophages and the crucial aspects influencing the success of phage therapy. However, despite their efficacy and safety, there is still no specific legislation that regulates their use. In the second part of this review, we describe the comprehensive research done in the past and recent years to address the use of phage therapy for the treatment and prevention of bacterial disease affecting domestic animals as an alternative to antibiotic treatments. While in farm animals, phage therapy efficacy perspectives have been widely studied in vitro and in vivo, especially for zoonoses and diseases linked to economic losses (such as mastitis), in pets, studies are still few and rather recent.
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Katayama, Erryk Stephan, Jonathan J. Hue, David Lawrence Bajor, Lee Mayer Ocuin, John Brian Ammori, Jeffrey Hardacre, and Jordan Michael Winter. "Clinical trials in pancreatic cancer: A comprehensive analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16730-e16730. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16730.
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e16730 Background: Pancreatic cancer is the most aggressive of common cancers and desperately in need of novel therapies. Unlike many other common cancers, there have been no new paradigm-changing therapies in the past 40 years beyond chemotherapy. The most urgent question in the field then is what is coming down the pike? In this study, we perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies. Methods: We queried clinicaltrials.gov for registered pancreatic cancer clinical trials. Studies were curated and categorized according to the phase of study, the clinical stage of the study population, the type of the intervention under investigation, and the biologic mechanism targeted by the therapy. This compendium revealed the full landscape of investigational therapeutic trials. Results: As of May 18, 2019, there were 440 total trials testing 600 distinct interventions. 104 of these trials spanned multiple phases, yielding 544 trials across phases. These included 38 trials (8.6%) in phase III testing, 269 (61%) in phase II, and 237 (54%) in phase I. With respect to therapeutic category, 186 (31%) were investigating immunotherapies, 66 (11%) targeted cell signaling pathways, 140 (23%) targeted cell cycle or DNA biology, and 32 (5%) targeted metabolic pathways. Of the 38 phase III trials, only 10 are currently testing novel drugs that are not already FDA approved or routinely used in patients for another indication. Conclusions: A large number of novel therapeutic strategies are currently under investigation. They include a broad range of therapies targeting diverse biologic processes. However, only a small number of novel therapies are in late-stage testing, suggesting that future progress is likely several years away, and dependent on the success of early-stage trials. [Table: see text]
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Aimar, Giacomo, Chiara Paratore, Clizia Zichi, Donatella Marino, Elisa Sperti, Andrea Caglio, Teresa Gamba, Francesca De Vita, and Massimo Di Maio. "A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?" Exploration of Targeted Anti-tumor Therapy 2, no. 5 (October 31, 2021): 448–64. http://dx.doi.org/10.37349/etat.2021.00056.
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Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.
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Duhoux, Francois P., and Jean-Pascal Machiels. "Antivascular Therapy for Epithelial Ovarian Cancer." Journal of Oncology 2010 (2010): 1–16. http://dx.doi.org/10.1155/2010/372547.
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Ovarian cancer is the fifth largest cancer killer in women. Improved understanding of the molecular pathways implicated in the pathogenesis of ovarian cancer has led to the investigation of novel targeted therapies. Ovarian cancer is characterized by an imbalance between pro- and antiangiogenic factors in favor of angiogenesis activation. Various antivascular strategies are currently under investigation in ovarian cancer. They can schematically be divided into antiangiogenic and vascular-disrupting therapies. This paper provides a comprehensive review of these new treatments targeting the tumor vasculature in this disease. Promising activities have been detected in phase II trials, and results of phase III clinical trials are awaited eagerly.
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Xu, David S., and Francisco A. Ponce. "Deep brain stimulation for dementias." Neurosurgical Focus 45, no. 2 (August 2018): E8. http://dx.doi.org/10.3171/2018.5.focus18172.
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OBJECTIVEThe aim of this article is to review the authors’ and published experience with deep brain stimulation (DBS) therapy for the treatment of patients with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD).METHODSTwo targets are current topics of investigation in the treatment of AD and PDD, the fornix and the nucleus basalis of Meynert. The authors reviewed the current published clinical experience with attention to patient selection, biological rationale of therapy, anatomical targeting, and clinical results and adverse events.RESULTSA total of 7 clinical studies treating 57 AD patients and 7 PDD patients have been reported. Serious adverse events were reported in 6 (9%) patients; none resulted in death or disability. Most studies were case reports or Phase 1/2 investigations and were not designed to assess treatment efficacy. Isolated patient experiences demonstrating improved clinical response after DBS have been reported, but no significant or consistent cognitive benefits associated with DBS treatment could be identified across larger patient populations.CONCLUSIONSPDD and AD are complex clinical entities, with investigation of DBS intervention still in an early phase. Recently published studies demonstrate acceptable surgical safety. For future studies to have adequate power to detect meaningful clinical changes, further refinement is needed in patient selection, metrics of clinical response, and optimal stimulation parameters.
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Jenei, Kristina, Alyson Haslam, Timothée Olivier, Milos Miljkovíc, and Vinay Prasad. "What drives cancer clinical trial accrual? An empirical analysis of studies leading to FDA authorisation (2015–2020)." BMJ Open 12, no. 10 (October 2022): e064458. http://dx.doi.org/10.1136/bmjopen-2022-064458.
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ObjectiveTo examine factors associated with accrual rate in industry sponsored clinical trials supporting US Food and Drug Administration (FDA) cancer drug approvals from 2015 to 2020.Design, setting and participantsRetrospective cross-sectional study included 194 pivotal trials supporting cancer drug approvals by the US FDA from 2015 to 2020.InterventionsClinical trials were analysed for the type of blinding, primary endpoint, whether crossover was specified in the publication, study phase, line of therapy, response rate, investigational sites, manufacturer and randomisation ratio.Main outcome measuresThe main outcome was the rate of accrual, which is the number of patients accrued in the study per open month of enrolment.ResultsThe study consisted of 133 randomised (68%) and 61 (32%) non-randomised clinical trials. In randomised studies, we found the accrual rate was higher in trials investigating first and second line drugs (adjusted rate ratios (aRR): 1.55, 95% CI 1.18 to 2.09), phase III trials (aRR: 2.13, 95% CI 1.48 to 2.99), and for studies sponsored by Merck (aRR: 1.47, 95% CI 1.18 to 2.37), adjusting for other covariates. In contrast, the primary endpoint of a study, presence of crossover, single agent response rate, the number of investigational sites, population disease burden and skewed randomisation ratios were not associated with the rate of accrual. In the non-randomised adjusted model, the accrual rate was 2.03 higher (95% CI 1.10 to 3.92) for clinical trials sponsored by manufacturer, specifically Merck. Primary endpoint, crossover, trial phase, response rate, the number of investigational sites, disease burden or line of therapy were not associated with the rate of accrual.ConclusionIn this cross-sectional study, line of therapy, study phase and manufacturer were the only factors associated with accrual rate. These findings suggest many proffered factors for speedy trial accrual are not associated with greater enrolment rates.
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Ratnayake, Gihan, James Larkin, and Lisa Pickering. "Advances in the Treatment Options for Kidney Cancer— Is There an Optimal Regimen?" Oncology & Hematology Review (US) 05, no. 01 (2009): 78. http://dx.doi.org/10.17925/ohr.2009.05.1.78.
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Treatment of renal cell carcinoma had long been hindered by poor responses to standard chemotherapeutic agents. Immunological modulators have some activity in metastatic disease but with considerable treatment-associated morbidity. Recent years have resulted in a shift in the treatment of advanced renal cell carcinoma towards novel targeted agents. Pivotal phase III trials involving bevacizumab, sorafenib, sunitinib, and temsirolimus have demonstrated improved disease control over the previous standards of first-line cytokine therapy and second-line palliative care. These trials have led to a change in routine practice in metastatic disease and the development of internationally accepted treatment algorithms. However, an optimal treatment paradigm has not yet been established: the role of combination therapy and the sequential use of these agents, and new investigational agents, remains the subject of ongoing investigation. In addition, these novel agents are being evaluated in the adjuvant and neoadjuvant settings.
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Іvanova, Yu V., S. M. Gramatyuk, І. A. Kryvoruchko, O. O. Zarudnyi, and K. V. Miasoiedov. "Photodynamic therapy in treatment of trophic ulcers in patients, suffering chronic venous insufficiency." Klinicheskaia khirurgiia 88, no. 7-8 (November 28, 2021): 32–38. http://dx.doi.org/10.26779/2522-1396.2021.7-8.32.
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Objective. Elaboration of complex approach to treatment of trophic ulcers of venous etiology, using photodynamical tissue therapy and modern types of the wound coverage.
Materials and methods. Into the investigation 24 patients were included, suffering venous ulcers on background of postthrombophlebitic disease and ageing from 31 to 79 yrs old. Into the comparison group there were included 14 patients, in whom a standard treatment (venotonic preparations, elastic compression, local application of multicomponent ointments depending on the wound phase present) was used. Into the main group10 patients were included, in whom the elaborated procedure of photodynamical therapy was applied. In treatment of the patients the Korobov’s photonic matrix «Barva Flex», owing spectral diapason 700-630 nm, corresponding to red light, was applied. Gel «Levuderm» (6% gel 5-aminolevulinic acid phosphate, which constitutes a natural predecessor of endogenous photosensitizer protoporphyrin IX) was applied.
Results. Transition of the wound process to the second stage in the comparison group was durable, in 50% of patients epithelization did not complete up to 45th day of treatment. In the main group, under the impact of the treatment method proposed, the term of granulations appearance have had shortened as well as filling in of the wound by mature granulation tissue, and epithelization have accelerated by 29.8%, comparing with standard therapy.
Conclusion. This investigation owes a shortage because of insufficient volume of sampling. Thus, it is necessary to perform further controlled investigations to discover the mechanisms of basic impact of the 5-aminolevulinic acid photodynamical therapy on the wound healing process.
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Macdonald, Katherine E., Helen J. Stacey, Gillian Harkin, Lesley M. L. Hall, Matthew J. Young, and Joshua D. Jones. "Patient perceptions of phage therapy for diabetic foot infection." PLOS ONE 15, no. 12 (December 14, 2020): e0243947. http://dx.doi.org/10.1371/journal.pone.0243947.
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Infections of diabetic foot ulcers are common, generally recalcitrant and often complicated by antibiotic resistance. Alternative antimicrobial strategies are needed. Phage therapy is a promising alternative that is being rediscovered. Despite phage therapy’s 100-year history, there have been no investigations into patient thoughts and concerns. This study aimed to explore patient awareness of and concern about antibiotic resistance and gain insight into the perceptions of phage therapy among a patient group that could potentially benefit from phage therapy. Patients with an active or resolved (healed or amputated) diabetic foot ulcer were eligible to participate. A survey was distributed digitally to eligible patients across Scotland via the NHS Research Scotland Diabetes Network and hard copies were available in diabetic foot clinics at the Royal Infirmary of Edinburgh and Queen Elizabeth University Hospital, Glasgow. A focus group of five survey respondents was held in Glasgow. Fifty-five survey responses were obtained. There was a high level of awareness (76.4%; N = 55) and concern (83.3%; N = 54) about antibiotic resistance. While largely aware of viruses, most patients had not heard of phage or phage therapy. Patients were no more concerned about phage than antibiotic therapy, with most suggesting more information could alleviate any concerns. Patient acceptability of phage therapy was high, a finding confirmed by the focus group. Patients are concerned about antibiotic resistance and supportive of ‘new’ antimicrobials. We have demonstrated that patients are supportive, enthusiastic and accepting of phage therapy. Although ‘Western’ phage therapy remains in its infancy, an understanding of patient ideas, concerns and expectations will be important in eventually shaping and successfully reintroducing phage therapy.
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Johnston, G. R., Linda Lauper, and C. N. Kobluk. "A Scintigraphic Investigation of Magnetic Field Therapy on the Equine Third Metacarpus." Veterinary and Comparative Orthopaedics and Traumatology 07, no. 01 (1994): 9–13. http://dx.doi.org/10.1055/s-0038-1633036.
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SummaryScintigraphy was performed in the vascular, soft tissue and bone phase to demonstrate increased blood flow resulting from the local application of a permanent magnetic pad on the equine third metacarpus using a crossover trial in eight horses.The results of the vascular phase showed a highly significant (p <0.01) increase in counts associated with magnet application. An increase in counts results from increased blood flow carrying more radionuclide to the area investigated. Fifteen of the sixteen limbs tested showed an increased vascular response. The soft tissue phase had a highly significant response (p = 0.01) with thirteen of the sixteen limbs showing increased activity. The bone phase also had a highly significant response (p <0.01) with fourteen of the sixteen limbs showing increased activity.This study shows that the Equinepad® applied to the third metacarpus of the horse increases the circulation and metabolic activity of the soft tissue and bone. These effects show some variability in degree and occur in the majority of limbs tested.Scintigraphy was performed in the vascular, soft tissue and bone phase using a cross over trial to demonstrate increased blood flow and metabolic activity as a result of the local application of a permanent magnetic pad on the equine metacarpus. A highly significant increase was evident in the three phases.
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Wang, Yicun, Shuohui Gao, Jiayin Lv, Yang Lin, Li Zhou, and Liying Han. "Phage Display Technology and its Applications in Cancer Immunotherapy." Anti-Cancer Agents in Medicinal Chemistry 19, no. 2 (May 31, 2019): 229–35. http://dx.doi.org/10.2174/1871520618666181029140814.
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Background:Phage display is an effective technology for generation and selection targeting protein for a variety of purpose, which is based on a direct linkage between the displayed protein and the DNA sequence encoding it and utilized in selecting peptides, improving peptides affinity and indicating protein-protein interactions. Phage particles displaying peptide have the potential to apply in the identification of cell-specific targeting molecules, identification of cancer cell surface biomarkers, identification anti-cancer peptide, and the design of peptide-based anticancer therapy.Method/Results:Literature searches, reviews and assessments about Phage were performed in this review from PubMed and Medline databases.Conclusion:The phage display technology is an inexpensive method for expressing exogenous peptides, generating unique peptides that bind any given target and investigating protein-protein interactions. Due to the powerful ability to insert exogenous gene and display exogenous peptides on the surface, phages may represent a powerful peptide delivery system that can be utilized to develop rapid, efficient, safe and inexpensive cancer therapy methods.
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Khatami, Ameneh, David A. Foley, Morgyn S. Warner, Elizabeth H. Barnes, Anton Y. Peleg, Jian Li, Stephen Stick, et al. "Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial." BMJ Open 12, no. 12 (December 2022): e065401. http://dx.doi.org/10.1136/bmjopen-2022-065401.
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IntroductionThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.Methods and analysisWe propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with highin vitroactivity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics.Ethics and disseminationParticipant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/).Trial registration numberRegistered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).
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Bastille, Julie V., and Kathleen M. Gill-Body. "A Yoga-Based Exercise Program for People With Chronic Poststroke Hemiparesis." Physical Therapy 84, no. 1 (January 1, 2004): 33–48. http://dx.doi.org/10.1093/ptj/84.1.33.
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AbstractBackground and Purpose. This was a preliminary investigation of the effects of a yoga-based exercise program on people with chronic (greater than 9 months) poststroke hemiparesis. Many people who have had a stroke report an impaired health status because of a reduced level of activity. Proponents of yoga contend that it offers a gentle alternative exercise program that can be easily adapted for people who have had a stroke. Subjects and Methods. Four subjects with chronic poststroke hemiparesis participated in this single-case study. The primary outcome measures were the Berg Balance Scale (BBS) and the Timed Movement Battery (TMB). A secondary outcome measure was the Stroke Impact Scale (SIS). The baseline testing phase varied for each subject and ranged from 4 to 7 weeks. The 8-week intervention phase consisted of 1.5-hour yoga sessions, 2 times per week, in the subject's home. The primary outcome data were collected each week, and the secondary outcome data were collected before the baseline testing phase and before and after the intervention phase. Results. Subjects 1, 2, and 4 had improved TMB scores, and subjects 3 and 4 had improved BBS scores. Discussion and Conclusion. The results suggest that yoga may be beneficial to people who have had a stroke. Further investigation is warranted to further examine the effects of yoga in this population.
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Chatterjee, Aradeep, Sudin Bhattacharya, Ashim Kumar Chatterjee, Amitava Chakraborty, Radhe S. Bhakta, and Jaydip Biswas. "A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with metastatic bladder cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15520-e15520. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15520.
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e15520 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating metastatic bladder cancer (MBC). Methods: Our study was phase II, open level, single arm and single stage. Participants’ eligibility criteria included (1) pathological confirmation of the malignancy (2) metastatic disease status (3) no prior conventional cancer treatments (4) Karnofsky performance status between 40- 70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2yrs, 3yrs, 4yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.04ml/ Kg body weight/ day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 72 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 6 (8.33%) cases and partial response occurred in 25 (34.72%) cases. 55 (76.39%) of them survived at least 1yr, 42 (58.33%) survived at least for 2yrs, 28 (38.89%) survived at least 3yrs, 23 (31.94%) survived at least 4yrs, 17 (23.61%) survived at least 5yrs. These participants didn't received conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with MBC. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating metastatic bladder cancer to integrate it into the mainstream of oncology treatments.
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Feliciano, Josephine, and Jyoti Patel. "Treatment of Non-Small Cell Lung Cancer: Focus on Pemetrexed Disodium." Clinical Medicine Insights: Therapeutics 2 (January 2010): CMT.S5262. http://dx.doi.org/10.4137/cmt.s5262.
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Pemetrexed (Alimta, Eli Lilly) is a multi-targeted anti-folate originally approved for its use in malignant mesothelioma. Based on results from phase III clinical investigations, it is now approved for use as a single agent in the second-line setting and in combination with platinum therapy in the first-line setting for advanced non-small cell lung cancer. It is also under investigation in earlier stages of non small cell lung cancer including in the adjuvant setting and with radiation. It has shown to be particularly efficacious for non-squamous histology and is well tolerated. Toxicity includes, but is not limited to hematologic toxicity and gastrointestinal toxicity, which are minimized by vitamin B12 and folic acid supplementation. Recent analyses also suggest cost-effectiveness of this agent in patient with advanced, non-squamous cell non-small cell lung cancer.
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Geyer, Holly L., and Ruben A. Mesa. "Therapy for myeloproliferative neoplasms: when, which agent, and how?" Blood 124, no. 24 (December 4, 2014): 3529–37. http://dx.doi.org/10.1182/blood-2014-05-577635.
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Abstract Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.
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Geyer, Holly L., and Ruben A. Mesa. "Therapy for myeloproliferative neoplasms: when, which agent, and how?" Hematology 2014, no. 1 (December 5, 2014): 277–86. http://dx.doi.org/10.1182/asheducation-2014.1.277.
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Abstract Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.
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Saez, R., J. B. Craig, J. G. Kuhn, G. R. Weiss, J. Koeller, J. Phillips, K. Havlin, G. Harman, J. Hardy, and T. J. Melink. "Phase I clinical investigation of amonafide." Journal of Clinical Oncology 7, no. 9 (September 1989): 1351–58. http://dx.doi.org/10.1200/jco.1989.7.9.1351.
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Amonafide (benzisoquinolinedione, NSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (less than or equal to 250 microliters) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness, and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses greater than or equal to 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponetially with a terminal harmonic mean terminal half-life (t 1/2) of 5.5 h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5% of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to amonafide is 918 mg/m2 with dose escalation to myelotoxicity.
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Mpilla, Gabriel, Amro Aboukameel, Irfana Muqbil, Steve Kim, Rafic Beydoun, Philip A. Philip, Ramzi M. Mohammad, et al. "PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors." Cancers 11, no. 12 (November 29, 2019): 1902. http://dx.doi.org/10.3390/cancers11121902.
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Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.
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Ozols, Robert F. "Counterpoint: Intraperitoneal Chemotherapy: An Investigational Treatment in Ovarian Cancer." Journal of the National Comprehensive Cancer Network 2, no. 6 (November 2004): 555–60. http://dx.doi.org/10.6004/jnccn.2004.0046.
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Intraperitoneal (IP) chemotherapy in ovarian cancer has been studied since 1978. Numerous phase II trials have been performed, which have shown that higher levels can be obtained in the peritoneal cavity compared with systemic circulation after administration of cytoxic agents in a large volume via a semi-permanent catheter. Three randomized trials have been performed in patients with ovarian cancer comparing different IP regimens to standard therapy with intravenous agents. The last two trials from the Gynecologic Oncology Group (GOG) and the Southwest Oncology Group (SWOG) compared two different IP regimens versus standard therapy with intravenous cisplatin plus paclitaxel. Although an improvement in progression-free survival was reported for the IP regimens, they have been associated with unacceptable toxicity, and no IP regimen can be considered standard therapy. Maintenance therapy with IP cisplatin also failed to improve survival in patients who obtained complete remission after intravenous chemotherapy. The GOG is considering another phase III trial of IP therapy that will compare a carboplatin-based regimen versus standard therapy with intravenous paclitaxel plus carboplatin. Unless such a trial shows an improvement in clinical outcome, intravenous carboplatin plus paclitaxel remains the standard of care and IP chemotherapy should not be used outside of a clinical trial.
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Michelson, Alan D. "Advances in Antiplatelet Therapy." Hematology 2011, no. 1 (December 10, 2011): 62–69. http://dx.doi.org/10.1182/asheducation-2011.1.62.
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Abstract Because of the central role of platelets in cardiovascular atherothrombosis, there is a well-established therapeutic role for antiplatelet therapy that includes aspirin (a cyclooxygenase 1 [COX1] inhibitor), clopidogrel (an antagonist of the ADP P2Y12 receptor), and the GPIIb-GPIIIa (αIIbβ3) antagonists. However, there remains a significant incidence of arterial thrombosis in patients treated with currently available antiplatelet therapy. Novel P2Y12 antagonists such as the recently US Food and Drug Administration (FDA)–approved prasugrel, along with ticagrelor, cangrelor, and elinogrel, have advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function. Currently ongoing phase 3 studies will determine whether these new P2Y12 antagonists will result in better and/or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects, as has been recently reported in some clinical settings for prasugrel and ticagrelor. Antagonists of the thrombin receptor protease-activated receptor 1 (PAR1) are also undergoing phase 3 trials, and many other novel antiplatelet agents are under investigation as antithrombotic agents.
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Blum, William, Kate Donohue, Guido Marcucci, Daniel J. DeAngelo, Geoffrey L. Uy, Bayard L. Powell, Wendy Stock, et al. "Challenges for Conducting Clinical Trials Evaluating Maintenance Chemotherapy In Acute Myeloid Leukemia (AML): a Cancer and Leukemia Group B (CALGB) Study." Blood 116, no. 21 (November 19, 2010): 2176. http://dx.doi.org/10.1182/blood.v116.21.2176.2176.
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Abstract Abstract 2176 Recent advances in frontline therapy for newly diagnosed AML include increased dose of anthracycline during induction, multi-agent regimens, high dose cytarabine (HiDAC) as consolidation for core binding factor (CBF) patients (pts), and allogeneic transplantation (alloHCT) during 1st remission for poor risk pts. Prolonged low-dose cytotoxic maintenance therapy does not appear to improve clinical outcomes, but investigation of novel maintenance strategies remains appealing, affording pts an opportunity to receive new therapies without increasing the considerable toxicities of induction/ consolidation. The CALGB performed a phase II study of induction and risk-adapted consolidation, followed by one year of maintenance therapy with decitabine, for newly diagnosed AML pts <60 years of age (CALGB 10503). Induction was daunorubicin 90 mg/m2 for 3 days, etoposide 100 mg/m2 for 3 days, and cytarabine 100 mg/m2 for 7 days (3+3+7). Reinduction (2+2+5) was given for residual disease on day 14. CBF pts in CR received 3 cycles of HiDAC; all other pts received autologous transplantation (autoHCT) if eligible, or HiDAC if not. Poor risk pts in 1st CR received alloHCT off study, when appropriate. Maintenance decitabine (20mg/m2 intravenously for 4–5 days, every 6 weeks for 8 cycles) began within 60–90 days after consolidation for pts with neutrophil ≥1000/uL and platelets ≥75,000/uL. Clinical results for the efficacy of decitabine maintenance for one year are not yet mature; the study closed to accrual July 30, 2010. In a previous study for a slightly more favorable patient cohort that was treated with identical induction and consolidation (CALGB 19808), 29% of all enrolled pts (214/732) and 39% of CR pts were registered to a randomized investigational maintenance therapy. To examine the feasibility of conducting a subsequent randomized trial of maintenance therapy, we analyzed reasons for study discontinuation for all pts enrolled on CALGB 10503; 473 pts had “response” or “off study” data forms submitted, to date. Complete remission* (CR) was achieved in 349 (74%). Reasons for induction failure were primary refractory AML (15%), induction death (5%), and other (6%, including those withdrawn from protocol for alternative therapy presumably due to persistent disease). The most common reason for not receiving maintenance therapy was the presence of AML, either primary refractory as noted or early relapse (7% of CR pts). In pts who achieved CR, the most common reason for not receiving maintenance was removal from the protocol for alloHCT (71/349, 20%). 9% refused further protocol therapy after consolidation, perhaps from “treatment fatigue.” Correlative investigations for CALGB 10503 are ongoing, including identification of novel prognostic markers, targets for treatment, and markers of minimal residual disease. Clearly, clinical investigation of maintenance therapy as part of a comprehensive treatment approach for frontline therapy of AML (inclusive of homogeneous induction and consolidation therapy) requires considerable up-front enrollment in order to reach maintenance accrual goals. Randomized maintenance studies will likely need intergroup participation for timely completion. However, we conclude that the benefits of up-front enrollment (relative to a post-consolidation enrollment strategy) outweigh the accrual burdens. Benefits include uniform pre-maintenance therapy and the potential for novel discovery from correlative studies. Study designs for future maintenance trials for AML in 1st CR must balance expediency with the more comprehensive approach employed in CALGB 10503. Disclosures: Blum: Celgene: Research Funding. Off Label Use: decitabine in AML. DeAngelo: Deminimus: Consultancy.
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Morris, Zachary S., and Paul M. Harari. "Interaction of Radiation Therapy With Molecular Targeted Agents." Journal of Clinical Oncology 32, no. 26 (September 10, 2014): 2886–93. http://dx.doi.org/10.1200/jco.2014.55.1366.
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The development of molecular targeted therapeutics in oncology builds on many years of scientific investigation into the cellular mechanics of malignant transformation and progression. The past two decades have brought an accelerating pace to the clinical investigation of new molecular targeted agents, particularly in the setting of metastatic disease. The integration of molecular targeted agents into phase III clinical trial design has lagged in the curative treatment setting, particularly in combination with established therapeutic modalities such as radiation. In this review, we discuss the interaction of radiation and molecular targeted therapeutics. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with molecular targeted agents that may go unrecognized with conventional screening and monotherapy clinical testing of novel agents. By using epidermal growth factor receptor (EGFR) as a primary example, we discuss recent clinical studies that illustrate the potential synergy of molecular targeted agents with radiation and highlight the clinical value of such interactions. For various molecular targeted agents, their greatest clinical impact may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach appear highly warranted.
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Kakabaraie, Kayvan. "The Effectiveness of Problem-Solving Therapy on Anxiety in Patients with Diabetes." Clinical Research and Clinical Trials 6, no. 2 (June 27, 2022): 01–04. http://dx.doi.org/10.31579/2693-4779/102.
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Background and purpose: This study aimed at investigating the effectiveness of problem-solving therapy on anxiety. Diabetes is a chronic disease with an increasing prevalence. Psychiatric problems are more common in diabetic patients than in the general population, affecting the prognosis and success of treatment. Problem-solving therapy is a short-term psychological intervention that can be used alone or with other therapeutic approaches. Methods: This case study was performed on four patients with diabetes who were selected based on available sampling. The DASS-21 questionnaire, which was answered by the subjects during three stages of pre-test, post-test, and two months after training as a follow-up, was used to collect data. First, these patients responded to the questionnaire in the baseline. Then, they were treated for problem-solving therapy for six sessions of 90 minutes and then answered again. Results: The studied data through descriptive statistics and analysis of variance with repeated measures showed that the score of individuals in the post-test stage had a significant decrease on this scale. A review of the data collected in the follow-up phase shows that problem-oriented treatment somewhat reduces anxiety and the resulting changes are relatively stable.
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Chatterjee, Aradeep, Sudin Bhattacharya, Ashim Kumar Chatterjee, Amitava Chakraborty, and Jaydip Biswas. "A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with unresectable metastatic colorectal carcinoma." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 407. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.407.
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407 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating unresectable metastatic colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open level, single arm and single stage. Participants eligibility criteria included (1) histopathology confirmation of the malignancy (2) metastatic and unresectable disease status (3) no prior conventional cancer treatments (4) Karnofsky performance status between 40–70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti-cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml/kg body weight/day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 105 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 12 (11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 (72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 yrs and 37 (35.24%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with UMCRC. The investigational drug psorinum is non-toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating unresectable metastatic colorectal carcinoma to integrate it into the mainstream of oncology treatments.
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Chatterjee, Aradeep, Amitava Chakraborty, Sudin Bhattacharya, Radhe S. Bhakta, Ashim Kumar Chatterjee, and Jaydip Biswas. "A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with unresectable metastatic colorectal carcinoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 2581. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2581.
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2581 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating unresectable metastatic colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open level, single arm and single stage. Participants eligibility criteria included (1) histopathology confirmation of the malignancy (2) metastatic and unresectable disease status (3) No prior conventional cancer treatments (4) Karnofsky performance status between 40 – 70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 105 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 12 (11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 (72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 yrs and 37 (35.24%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with UMCRC. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating unresectable metastatic colorectal carcinoma to integrate it into the mainstream of oncology treatments.
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Gardner, Frank H. "Anabolic steroids in aplastic anemia." Acta Endocrinologica 110, no. 3_Suppla (December 1985): S87—S96. http://dx.doi.org/10.1530/acta.0.109s0087.
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Abstract. Despite the successful recovery of young patients with aplastic anemia following bone marrow transplants, additional patients have had benefit from immune suppression therapy, predominantly antithymus globulin (ATG). There exists a large residual pool of patients who have not been able to benefit from these modalities because of 1) lack of compatible siblings, 2) age, 3) duration of illness prior to diagnosis. Historically oral androstanes have been helpful in the treatment of chronic aplastic anemia. The long-range survival in large cooperative groups of patients treated with androstanes have indicated that both severe and chronic aplastic anemia have had responses similar to immune suppressive therapy. There is a need to have further investigations to seek the most effective anabolic agents. Many group studies have shortened treatment schedules when an erythropoietic response has been obtained, rather than continue therapy until the maximum platelet count is achieved. Such abbreviation of therapy may hasten a hematological relapse. Clinics also should evaluate parenteral androstanes since they appear to be more hematopoietic. Also the investigation of different androstane metabolites, i.e. etiocholanolone, should be pursued to determined if a more effective stimulus of stem cell proliferation can be achieved. In the recovery phase of the aplastic anemia patients treated with immune suppression or androstanes the peripheral blood reflects an altered proliferation of the marrow stem cell. The majority of these patients continue to have abnormalities in red cells (macrocytosis) and decreased platelet size.
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Cresswell, Fiona V., Kenneth Ssebambulidde, Daniel Grint, Lindsey te Brake, Abdul Musabire, Rachel R. Atherton, Lillian Tugume, et al. "High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study)." Wellcome Open Research 3 (July 10, 2018): 83. http://dx.doi.org/10.12688/wellcomeopenres.14691.1.
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Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24th April 2018)
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Chatterjee, Aradeep, Sudin Bhattacharya, Amitava Chakraborty, Radhe S. Bhakta, Ashim Kumar Chatterjee, and Jaydip Biswas. "A phase II, single-arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with advanced esophageal carcinoma." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 62. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.62.
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62 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating advanced esophageal carcinoma (ECA). Methods: Our study was phase- II, open level, single arm and single stage. Participants’ eligibility criteria included (1) histopathology confirmation of ECA (2) inoperable tumor (3) no prior conventional cancer treatments (4) karnofsky performance status between 40 -70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 65 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 11 (16.92%) case and partial response occurred in 20 (30.77%) cases. 44 (67.69%) of them survived at least 1 yr, 32 (49.23%) survived at least 2 yrs, 24 (36.92%) survived at least 3 yrs, 21 (32.31%) survived at least 4 yrs and 17 (26.15%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. According to AJCC TNM staging system, 31 (47.69%) participants diagnosed at stage IV. Among them complete response observed in 4 (12.90%) cases, partial response observed in 8 (25.81%) cases and 5 (16.13%) of them survived at least 5 yrs. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with advanced ECA. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating esophageal cancer.
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Kennedy, LMT, BCTMB, DrPH, Ann Blair. "Getting to Phase 3: an Interview with Virginia S. Cowen, PhD, LMT." International Journal of Therapeutic Massage & Bodywork: Research, Education, & Practice 10, no. 4 (December 5, 2017): 1. http://dx.doi.org/10.3822/ijtmb.v10i4.392.
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I feel that it is important to know the stories behind those who are working hard in the field to bring forward massage therapy research. Interviews with massage therapy researchers will now occasionally be included in the Journal as a new editorial feature. The first interview is with Virginia S. Cowen, PhD, LMT a New York State-licensed and NCB board-certified massage therapist with a PhD from Arizona State. She first became interested in massage therapy research while in massage therapy school, and her most recent work is investigating the integration of massage therapy into medical settings. Dr. Cowen states that massage therapy needs to move to Phase 3 research, and aligning with massage therapy practice and research on massage therapy education are areas ripe for research development. She urges the massage therapy profession to work together to develop clinical practice guidelines which could help move the profession forward.
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Vuong, Te, Aurelie Garant, Veronique Vendrely, Remi Nout, André-Guy Martin, Shirin A. Enger, Ervin Podgorsak, Belal Moftah, and Slobodan Devic. "Image-Guided Brachytherapy for Rectal Cancer: Reviewing the Past Two Decades of Clinical Investigation." Cancers 14, no. 19 (October 4, 2022): 4846. http://dx.doi.org/10.3390/cancers14194846.
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(1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community’s work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4–6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer.
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Andriolo, Jessica M., Nathan J. Sutton, John P. Murphy, Lane G. Huston, Emily A. Kooistra-Manning, Robert F. West, Marisa L. Pedulla, M. Katie Hailer, and Jack L. Skinner. "Electrospun Fibers for Controlled Release of Nanoparticle-Assisted Phage Therapy Treatment of Topical Wounds." MRS Advances 3, no. 50 (2018): 3019–25. http://dx.doi.org/10.1557/adv.2018.483.
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ABSTRACTBacterial cultures exposed to iron-doped apatite nanoparticles (IDANPs) prior to the introduction of antagonistic viruses experience up to 2.3 times the bacterial destruction observed in control cultures. Maximum antibacterial activity of these bacteria-specific viruses, or phage, occurs after bacterial cultures have been exposed to IDANPs for 1 hr prior to phage introduction, demonstrating that IDANP-assisted phage therapy would not be straight forward, but would instead require controlled time release of IDANPs and phage. These findings motivated the design of an electrospun nanofiber mesh treatment delivery system that allows burst release of IDANPs, followed by slow, consistent release of phage for treatment of topical bacterial infections. IDANPs resemble hydroxyapatite, a biocompatible mineral analogous to the inorganic constituent of mammalian bone, which has been approved by the Food and Drug Administration for many biomedical purposes. The composite nanofiber mesh was designed for IDANP-assisted phage therapy treatment of topical wounds and consists of a superficial, rapid release layer of polyethylene oxide (PEO) fibers doped with IDANPs, followed by inner, coaxial polycaprolactone / polyethylene glycol (PCL/PEG) blended polymer fiber layer for slower phage delivery. Our investigations have established that IDANP-doped PEO fibers are effective vehicles for dissemination of IDANPs for bacterial exposure and resultant increased bacterial death by phage. In this work, slower delivery of the phage behind IDANPs was accomplished using coaxial, electrospun fibers composed of PCL/PEG polymer blend.