Cancer is a leading cause of deaths in the world. Cytotoxic drugs, target-specific drugs and peptide drugs are major types of the anticancer drugs. Cisplatin, a cytotoxic anticancer drug, is the most common platinum-based chemotherapeutic drug used in clinics. However, this drug has fatal side effects because of its nonspecific toxicity. In this thesis I report the development of platinum (IV) prodrugs conjugated with cancercell-specific peptides and demonstrated its specificity, cytotoxicity and apoptotic effects towards their respective target cancer cell lines. I further showed that similar to cisplatin (platinum (II) drug), the cell-specific cytotoxic mechanism of the new compounds is crosslinking of DNA. In addition to using peptide-conjugated small molecules for improving specificity, I developed peptide-based, anti-angiogenesis inhibitors for targeted therapy. Angiogenesis plays a key role in cancer growth, survival and metastasis. Clinically it has been shown that employing anti-angiogenesis inhibitors in combinational therapy with traditionally chemotherapeutic agents produce significantly better results. Human methionine aminopeptidase 2 (hMetAP2) removes N-terminal methionine (the start codon) from nascent allowing them to interact with the α subunit of eukaryotic initiation factor 2. It plays an active role in protein synthesis, cell proliferation, and angiogenesis. Thus, hMetAP2 has been an attractive drug target not only for cancers but also for chronic disorders such as agerelated macular degeneration, rheumatoid arthritis, obesity, and type-2 diabetes. Using computational tools, I designed a self-derived structural disrupting peptide drug targeting hMetAP2. In this thesis I show that this peptide can specifically inhibit the activity of hMetAP2 but not those of other human methionine aminopeptidases (hMetAP1 or hMetAP1D) in extracts of breast carcinoma cells (MCF7 and SKBR3). The liposome-delivered peptide inhibits hMetAP2 by changing its conformational state according to semi-native pulsed field gel electrophoresis (PAGE) and causes cell cycle arrest. The peptide delivered by either liposome or a cell-penetration peptide can inhibit cell proliferation, migration, and wound healing of both breast (MCF7) and colon (SW48, SW480) cancer cells with a lesser effect on non-neoplastic colon epithelial cells (FHC). Thus, the self-derived peptide from hMetAP2 could be useful as a new anti-angiogenesis agent for targeting cell growth and associated disorders.
CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL.Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively.Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3-4) ICANS. Median time to development of ICANS was 5 days (range, 3-11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS.ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.
A 60 year old woman with migraine, hypertension, and recently diagnosed temporal lobe epilepsy presented to the memory clinic with progressive memory impairment and …
Some evidence supports the use of a short list of essential medicines to improve prescribing. We aimed to create a preliminary essential medicines list for use in Canada.The 2013 World Health Organization Model List of Essential Medicines was initially adapted by the research team. Fourteen Canadian clinicians gave suggestions for changes to the list. Literature relevant to each unique suggestion was gathered and presented to 3 clinician-scientists who used a modified nominal group technique to make recommendations on the suggested changes. Audits of prescriptions of 2 Toronto-based family health teams (an inner city clinic and a suburban site) between Aug. 1, 2013, and July 30, 2014, were performed to identify common prescriptions that were not on the draft list. Literature relevant to these additional medications was gathered and shared with the clinician-scientist review panel to determine whether each should be added to the list, and a list was developed. The audits were repeated based on the final list to provide a preliminary assessment of the coverage of the list.The multistep process produced a list of 125 medications. The medications included on this list covered 90.8% and 92.6% of prescriptions at the inner city clinic and the suburban site, respectively. In total, 93% of the patients seen at the inner city clinic and 96% of the patients seen at the suburban clinic had all or all but 1 of their medications covered by the list.A preliminary list of essential medicines was developed that covered most, but not all, prescriptions at 2 primary care sites. The list should be further refined based on wider input.
Abstract Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.
2061 Background: Symptomatic radiation neurotoxicity (RN), manifesting on MRI as focal necrosis and/or T2 signal abnormality, is a dreaded complication of radiation therapy (RT). While RT is standard of care for anaplastic gliomas, the long-term benefit vs risk profile in low-grade gliomas is not well defined. Patients with oligodendroglioma carry a better overall survival than those with astrocytoma. Anecdotally, they are more prone to experience RN than astrocytomas, as suggested by Acharya et al in 2017. We hypothesized that, independent of grade, oligodendrogliomas have a higher incidence of RN as compared to astrocytomas. Methods: We reviewed the records of 628 patients with WHO grade II and III gliomas from our institution. Study population comprised 326 patients with: standard fractionated RT, pathology confirmation by a neuropathologist, and follow up of at least 2 years after diagnosis. RN was defined as either histologically confirmed by pathology or requiring intervention for clinically presumed RN (bevacizumab or high-dose steroids.) A separate category included patients with dramatic cognitive decline with increased T2 signal abnormality, in the absence or tumor progression. Results: There were 131 patients with oligodendroglioma, based upon 1p/19q co-deletion (105 cases) or histology in the absence of molecular testing (26 cases). The remaining 195 patients had astrocytoma with intact 1p/19q, isocitrate dehydrogenase (IDH) wild-type, or diagnosed histologically absent molecular testing. The incidence of RN were 18.3% and 8.2% for oligodendroglioma and astrocytoma, respectively (p = 0.0063). An additional four patients with oligodendroglioma and two with astrocytoma had significant cognitive deterioration with increased T2 signal abnormality, without tumor progression. Conclusions: The greater than two-fold increase in RN incidence for oligodendrogliomas is significant and suggests patients with oligodendrogliomas may be more at risk to develop RN. Therefore, in patients with oligodendroglioma, the consideration of fractionated RT needs to be weighed against the increased potential for RN. Analysis of baseline imaging and patient characteristics variables that correlate with development of RN are ongoing and will be presented at the meeting.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)