A descriptive analysis of the contents of Care Response, an international data set of patient-reported outcomes for chiropractic patients.

BACKGROUND: Databases have become an important tool in understanding trends and correlations in health care by collecting demographic and clinical information. Analysis of data collected from large cohorts of patients can have the potential to generate insights into factors identifying treatments and the characteristics of subgroups of patients who respond to certain types of care. The Care Response (CR) database was designed to capture patient-reported outcome measures (PROMs) for chiropractic patients internationally. Although several papers have been published analysing some of the data, its contents have not yet been comprehensively documented. The primary aim of this study was to describe the information in the CR database. The secondary aim was to determine whether there was suitable information available to better understand subgroups of chiropractic patients and responsiveness to care. This would be achieved by enabling correlations among patient demographics, diagnoses, and therapeutic interventions with machine learning approaches. METHODS: Data in all available fields were requested with no date restriction. Data were collected on 12 April 2022. The output was manually scanned for scope and completeness. Tables were created with categories of information. Descriptive statistics were applied. RESULTS: The CR database collects information from patients at the first clinical visit, 14, 30, and 90 days subsequently. There were 32,468 patient responses; 3210 patients completed all fields through the 90 day follow up period. 45% of respondents were male; 54% were female; the average age was 49. There was little demographic information, and no information on diagnoses or therapeutic interventions. We received StartBack, numerical pain scale, patient global impression of change, and Bournemouth questionnaire data, but no other PROMs. CONCLUSIONS: The CR database is a large set of PROMs for chiropractic patients internationally. We found it unsuitable for machine learning analysis for our purposes; its utility is limited by a lack of demographic information, diagnoses, and therapeutic interventions. However, it can offer information about chiropractic care in general and patient satisfaction. It could form the basis for a useful clinical tool in the future, if reformed to be more accessible to researchers and expanded with more information collected.

Impact of audible pops associated with spinal manipulation on perceived pain: a systematic review.

OBJECTIVES: An audible pop is the sound that can derive from an adjustment in spinal manipulative therapy and is often seen as an indicator of a successful treatment. A review conducted in 1998 concluded that there was little scientific evidence to support any therapeutic benefit derived from the audible pop. Since then, research methods have evolved considerably creating opportunities for new evidence to emerge. It was therefore timely to review the evidence. METHODS: The following electronic databases were searched for relevant studies pertaining to the impact of audible pops in spinal manipulative therapy: PubMed, Index to Chiropractic Literature (ICL), Cumulative Index to Nursing & Allied Health Literature (CINAHL) and Web-of-Science. The main outcome was pain. Two reviewers independently selected studies, extracted data, and assessed risk of bias and quality of the evidence using the Downs and Black checklist. Results of the included literature were synthesized into a systematic review. RESULTS: Five original research articles were included in the review, of which four were prospective cohort studies and one a randomized controlled trial. All studies reported similar results: regardless of the area of the spine manipulated or follow-up time, there was no evidence of improved pain outcomes associated with an audible pop. One study even reported a hypoalgesic effect to external pain stimuli after spinal manipulation, regardless of an audible pop. CONCLUSIONS: Whilst there is still no consensus among chiropractors on the association of an audible pop and pain outcomes in spinal manipulative therapy, knowledge about the audible pop has advanced. This review suggests that the presence or absence of an audible pop may not be important regarding pain outcomes with spinal manipulation.

The global summit on the efficacy and effectiveness of spinal manipulative therapy for the prevention and treatment of non-musculoskeletal disorders: a systematic review of the literature.

BACKGROUND: A small proportion of chiropractors, osteopaths, and other manual medicine providers use spinal manipulative therapy (SMT) to manage non-musculoskeletal disorders. However, the efficacy and effectiveness of these interventions to prevent or treat non-musculoskeletal disorders remain controversial. OBJECTIVES: We convened a Global Summit of international scientists to conduct a systematic review of the literature to determine the efficacy and effectiveness of SMT for the primary, secondary and tertiary prevention of non-musculoskeletal disorders. GLOBAL SUMMIT: The Global Summit took place on September 14-15, 2019 in Toronto, Canada. It was attended by 50 researchers from 8 countries and 28 observers from 18 chiropractic organizations. At the summit, participants critically appraised the literature and synthesized the evidence. SYSTEMATIC REVIEW OF THE LITERATURE: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health, and the Index to Chiropractic Literature from inception to May 15, 2019 using subject headings specific to each database and free text words relevant to manipulation/manual therapy, effectiveness, prevention, treatment, and non-musculoskeletal disorders. Eligible for review were randomized controlled trials published in English. The methodological quality of eligible studies was assessed independently by reviewers using the Scottish Intercollegiate Guidelines Network (SIGN) criteria for randomized controlled trials. We synthesized the evidence from articles with high or acceptable methodological quality according to the Synthesis without Meta-Analysis (SWiM) Guideline. The final risk of bias and evidence tables were reviewed by researchers who attended the Global Summit and 75% (38/50) had to approve the content to reach consensus. RESULTS: We retrieved 4997 citations, removed 1123 duplicates and screened 3874 citations. Of those, the eligibility of 32 articles was evaluated at the Global Summit and 16 articles were included in our systematic review. Our synthesis included six randomized controlled trials with acceptable or high methodological quality (reported in seven articles). These trials investigated the efficacy or effectiveness of SMT for the management of infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. None of the trials evaluated the effectiveness of SMT in preventing the occurrence of non-musculoskeletal disorders. Consensus was reached on the content of all risk of bias and evidence tables. All randomized controlled trials with high or acceptable quality found that SMT was not superior to sham interventions for the treatment of these non-musculoskeletal disorders. Six of 50 participants (12%) in the Global Summit did not approve the final report. CONCLUSION: Our systematic review included six randomized clinical trials (534 participants) of acceptable or high quality investigating the efficacy or effectiveness of SMT for the treatment of non-musculoskeletal disorders. We found no evidence of an effect of SMT for the management of non-musculoskeletal disorders including infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. This finding challenges the validity of the theory that treating spinal dysfunctions with SMT has a physiological effect on organs and their function. Governments, payers, regulators, educators, and clinicians should consider this evidence when developing policies about the use and reimbursement of SMT for non-musculoskeletal disorders.

Chiropractors' views on the use of patient-reported outcome measures in clinical practice: a qualitative study.

Background: Patient-reported outcome measures (PROMs) are widely available for use in musculoskeletal care. However, there is little research exploring the implementation of PROMs in clinical practice. This qualitative study explored chiropractors' views on PROMs to identify any barriers and facilitators to implementing PROMs in chiropractic care and the training needs of chiropractors regarding the use of PROMs. Methods: A qualitative study of chiropractors' views on PROMs was undertaken as part of a larger project to address the feasibility of conducting a randomised controlled trial of PROM use in chiropractic clinics for patients with low back pain. Contact was made with chiropractors working in chiropractic companies with multiple clinic sites. Semi-structured interviews were conducted with eight chiropractors, either face-to-face at their place of work or over the telephone. The interviews were transcribed verbatim and analysed using thematic analysis. The data were coded inductively by two authors. Results: Chiropractors discussed their knowledge and engagement with PROMs in clinical practice, identifying reasons for their use, such as understanding clinic performance, clinical practice, and research. They also discussed how they used PROMs within their clinical practice and the benefits of using them with individual patients, for example during the consultation, identifying yellow flags, and tracking patient progress. Chiropractors voiced concerns about patient engagement with PROMs, questioning if patients find them burdensome, and the appropriate PROMs to use with patients with pain. Finally, chiropractors acknowledged the organisational barriers and facilitators to using PROMs within their practice, such as busy practices, electronic systems, and use of reception staff. Conclusions: Using participating chiropractors' views of PROMs, the study identified barriers and facilitators to implementing PROMs in chiropractic care, such as clinician knowledge, engagement, and organisational concerns and identified the potential training needs of chiropractors regarding PROMs. The results from the study suggested chiropractors use PROMs with their individual patients, but PROMs should be meaningful to patients and chiropractors to improve engagement.

Engagement as predictors of performance in a single cohort of undergraduate chiropractic students.

OBJECTIVE: To investigate the potential association of novel academic and nonacademic factors with chiropractic student academic performance. METHODS: Students enrolled into year 1 of a chiropractic master's degree (MChiro) at our college were selected for this study. Data collected included demographics, attendance, virtual learning environment use, additional learning needs, previous degree qualifications, and summative marks. Differences between students who had to take an examination more than once (resit) and nonresit students were explored using t test and χ2 analysis. Relationships between attendance and end-of-year marks were explored using regression analysis. RESULTS: Male students outperformed female students in four of the six units and as the total year average. Students who attended <80% of classes were more likely to have a resit in one or more units (relative risk [ RR] = 2.6; 95% confidence interval [CI], 1.4-4.9). Students who performed poorly (<70%) in the semester 1 unit of a course on human structure and failed the semester 1 practical assessment of a course on clinical management were significantly more likely to have one or more resit assessments in semester 2 units ( RR = 3.5 [95% CI, 2.2-5.7]; RR = 3.2 [95% CI, 2.0-4.9]). Attendance and unit 105 were independent predictors of one or more resits at the end-of-year ( R2 = 0.86, p < .001). CONCLUSION: Attendance and first semester summative marks were associated with end-of-year performance. As such, these markers of performance may be used to flag struggling students in the program.

TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation.

Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive treatment strategy for wild-type TP53 cancers. To determine how resistance to MDM2/p53 binding antagonists might develop, SJSA-1 and NGP cells were exposed to growth inhibitory concentrations of chemically distinct MDM2 inhibitors, Nutlin-3 and MI-63, and clonal resistant cell lines generated. The p53 mediated responses of parental and resistant cell lines were compared. In contrast to the parental cell lines, p53 activation by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines. An identical TP53 mutation was subsequently identified in both of the SJSA-1 resistant lines, whilst one out of three identified mutations was common to both NGP derived lines. Mutation specific PCR revealed these mutations were present in parental SJSA-1 and NGP cell populations at a low frequency. Despite cross-resistance to a broad panel of MDM2/p53 binding antagonists, these MDM2-amplified and TP53 mutant cell lines remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR.

Influence of year-on-year performance on final degree classification in a chiropractic master's degree program.

OBJECTIVE: We explored if any predictors of success could be identified from end-of-year grades in a chiropractic master's program and whether these grades could predict final-year grade performance and year-on-year performance. METHODS: End-of-year average grades and module grades for a single cohort of students covering all academic results for years 1-4 of the 2013 graduating class were used for this analysis. Analysis consisted of within-year correlations of module grades with end-of-year average grades, linear regression models for continuous data, and logistic regression models for predicting final degree classifications. RESULTS: In year 1, 140 students were enrolled; 85.7% of students completed the program 4 years later. End-of-year average grades for years 1-3 were correlated (Pearson r values ranging from .75 to .87), but the end-of-year grades for years 1-3 were poorly correlated with clinic internship performance. In linear regression, several modules were predictive of end-of-year average grades for each year. For year 1, logistic regression showed that the modules Physiology and Pharmacology and Investigative Imaging were predictive of year 1 performance (odds ratio [OR] = 1.15 and 0.9, respectively). In year 3, the modules Anatomy and Histopathology 3 and Problem Solving were predictors of the difference between a pass/merit or distinction final degree classification (OR = 1.06 and 1.12, respectively). CONCLUSION: Early academic performance is weakly correlated with final-year clinic internship performance. The modules of Anatomy and Histopathology year 3 and Problem Solving year 3 emerged more consistently than other modules as being associated with final-year classifications.

Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach.

Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.

Comparison of two methods of collecting healthcare usage data in chiropractic clinics: patient-report versus documentation in patient files.

BACKGROUND: The use of patient-reported questionnaires to collect information on costs associated with routine healthcare services, such as chiropractic, represents a less labour intensive alternative to retrieving these data from patient files. The aim of this paper was to compare patient-report versus patient files for the collection of data describing healthcare usage in chiropractic clinics. METHODS: As part of a prospective single cohort multi-centre study, data on the number of visits made to chiropractic clinics determined using patient-reported questionnaires or as recorded in patient files were compared three months following the start of treatment. These data were analysed for agreement using the Intraclass Correlation Coefficient (ICC) and the 95% Limits of Agreement. RESULTS: Eighty-nine patients that had undergone chiropractic care were included in the present study. The two methods yielded an ICC of 0.83 (95% CI = 0.75 to 0.88). However, there was a significant difference between the data collection methods, with an average of 0.6 (95% CI = 0.25 to 1.01) additional visits reported in patient files. The 95% Limits of Agreement ranged from 3 fewer visits to 4 additional visits in patient files relative to the number of visits recalled by patients. CONCLUSION: There was some discrepancy between the number of visits made to the clinic recalled by patients compared to the number recorded in patient files. This should be taken into account in future evaluations of costs of treatments.

The psychometric profile of chiropractic patients in Norway and England: using and comparing the generic versions of the STarT Back 5-item screening tool and the Bournemouth Questionnaire.

BACKGROUND: Musculoskeletal pain and low back pain (LBP) in particular is one of the more costly health challenges to society. The STarT Back Tool (SBT) has been developed in the UK with a view to identifying subgroups of LBP patients in order to guide more cost effective care decisions. The Bournemouth Questionnaire (BQ) is a validated multidimensional patient reported outcome measure (PROM) that is widely used in routine clinical practice settings. This study sets out to describe and compare SBT and BQ scores within and between populations of patients presenting for chiropractic care in Norway and Great Britain. METHODS: Patient demographics, BQ and the 5-item generic condition SBT data were collected from patients presenting with musculoskeletal pain to 18 Norwegian and 12 English chiropractors. Analysis of correlation between groups was achieved using a 1-way Chi2 approximation (p < 0.05). RESULTS: Eleven percent of Norwegian LBP patients (n = 214) and 24% of English LBP patients (n = 186) were "distressed by their condition" (SBT > 4). By comparison, Norwegian chiropractic patients are: somewhat younger, have lower BQ scores, are less distressed by the condition and score significantly lower on items relating to catastrophisation and depression than English patients. There was an apparent association between total BQ and SBT scores (correlation 0.59, p < .0001) and patients who scored higher than 45 (IQR 39-58) on BQ were more likely to respond "distressed by condition" (>4) on SBT. Furthermore, patients in "distressed by condition" SBT category who had marked the "low mood" question on SBT also had a high score on the "depression" question of BQ (>6 (IQR 4-8), correlation 0.54, p < .0001). CONCLUSION: The BQ and SBT appear to identify the same subgroups in some, but not all of the measured items. It appears that unknown factors result in variations between patients seeking chiropractic care for comparable complaints in primary care in England vs Norway. Comparison of populations from Norway and UK demonstrate that extrapolating and pooling of data in relation to different populations should be done with caution, in regard to these stratification tools.

Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer.

Ataxia telangiectasia mutated (ATM) kinase signals DNA double-strand breaks (DSB) to cell-cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo- and radiosensitization. KU59403 is an ATM inhibitor with the potency, selectivity, and solubility for advanced preclinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116, and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide, and doxorubicin. Chemo- and radiosensitization by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hours in tumor xenografts. KU59403 significantly enhanced the antitumor activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were nontoxic alone and well-tolerated in combination. Chemosensitization was both dose- and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to show good tissue distribution and significant chemosensitization in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle preclinical data to support the future clinical development of ATM inhibitors.

Efficacy of chiropractic manual therapy on infant colic: a pragmatic single-blind, randomized controlled trial.

OBJECTIVE: The purpose of this study was to determine the efficacy of chiropractic manual therapy for infants with unexplained crying behavior and if there was any effect of parental reporting bias. METHODS: Infants with unexplained persistent crying (infant colic) were recruited between October 2007 and November 2009 at a chiropractic teaching clinic in the United Kingdom. Infants younger than 8 weeks were randomized to 1 of 3 groups: (i) infant treated, parent aware; (ii) infant treated, parent unaware; and (iii) infant not treated, parent unaware. The primary outcome was a daily crying diary completed by parents over a period of 10 days. Treatments were pragmatic, individualized to examination findings, and consisted of chiropractic manual therapy of the spine. Analysis of covariance was used to investigate differences between groups. RESULTS: One hundred four patients were randomized. In parents blinded to treatment allocation, using 2 or less hours of crying per day to determine a clinically significant improvement in crying time, the increased odds of improvement in treated infants compared with those not receiving treatment were statistically significant at day 8 (adjusted odds ratio [OR], 8.1; 95% confidence interval [CI], 1.4-45.0) and at day 10 (adjusted OR, 11.8; 95% CI, 2.1-68.3). The number needed to treat was 3. In contrast, the odds of improvement in treated infants were not significantly different in blinded compared with nonblinded parents (adjusted ORs, 0.7 [95% CI, 0.2-2.0] and 0.5 [95% CI, 0.1-1.6] at days 8 and 10, respectively). CONCLUSIONS: In this study, chiropractic manual therapy improved crying behavior in infants with colic. The findings showed that knowledge of treatment by the parent did not appear to contribute to the observed treatment effects in this study. Thus, it is unlikely that observed treatment effect is due to bias on the part of the reporting parent.

Potent, selective inhibitors of fibroblast growth factor receptor define fibroblast growth factor dependence in preclinical cancer models.

We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.

Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM. METHODS: Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14)-negative human MM tumour xenograft models. RESULTS: PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI(50)=10 nM and 730 nM, versus GI(50) >1 µM and 2.7 µM for parental cells; p<0.0001) and t(4;14) positive MM cell lines (GI(50)=4-10 µM and 1-3 µM, versus GI(50)=14-15 µM and 4-5 µM for t(4;14) negative MM cells; p≤0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model. CONCLUSIONS: These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib.

Responsiveness of the Bournemouth questionnaire in determining minimal clinically important change in subgroups of low back pain patients.

STUDY DESIGN: Prospective single cohort. OBJECTIVE: To determine the ability of the Bournemouth Questionnaire (BQ) to distinguish between improved and nonimproved patients who present with either short (acute) or long (subacute/chronic) duration low back pain (LBP), and with either high or low baseline scores (severity). SUMMARY OF BACKGROUND DATA: Recent evidence suggests that the responsiveness of outcome measures used to determine clinical change is dependent on the chronicity and severity of the condition. METHODS: Data from 437 back patients undergoing chiropractic treatment were used for analysis. Patients completed the BQ before treatment and 4 weeks later. Patients also completed the Patient Global Impression of Change scale at follow-up. Responsiveness was determined by calculating Standardized Response Means (SRM) and by the area under the receiver operator curve (ROC) with best cut-point analysis. The minimal clinically important change (MCIC) was calculated by the change score with the best balanced sensitivity and specificity. RESULTS: The responsiveness of the BQ at 4 weeks was dependent on both duration and severity of the condition. As expected, the responsiveness of the total BQ was greater in improved compared to nonimproved patients in the acute (SRM [95% confidence interval], 1.9 [1.7-2.0] and 1.2 [0.9-1.5], respectively), as well as in the subacute/chronic group (SRM, 1.7 [1.5-1.8] and 0.5 [0.3-0.7]), respectively. For the psychological domains, SRMs in the acute patients failed to distinguish improved from nonimproved patients (SRM [95% confidence interval], 1.3 [1.1-1.4] and 0.9 [0.5-1.2] for anxiety, and 0.9 [0.8-1.0] and 0.8 [0.5-1.2] for depression). In acute and subacute/chronic patients, the MCIC for the total BQ was 26 and 18 points, respectively. In patients with lower and higher BQ scores at baseline, the MCIC was 10 and 31 points, respectively. CONCLUSION: The BQ can distinguish between improved and nonimproved LBP patients but the amount of change needed to achieve this is lower in more chronic patients and in individuals with less severe presentation at baseline.

Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.

Poly(ADP-ribose) polymerase (PARP)-1 (EC 2.4.2.30) is a nuclear enzyme that promotes the base excision repair of DNA breaks. Inhibition of PARP-1 enhances the efficacy of DNA alkylating agents, topoisomerase I poisons, and ionizing radiation. Our aim was to identify a PARP inhibitor for clinical trial from a panel of 42 potent PARP inhibitors (K(i), 1.4-15.1 nmol/L) based on the quinazolinone, benzimidazole, tricyclic benzimidazole, tricyclic indole, and tricyclic indole-1-one core structures. We evaluated chemosensitization of temozolomide and topotecan using LoVo and SW620 human colorectal cells; in vitro radiosensitization was measured using LoVo cells, and the enhancement of antitumor activity of temozolomide was evaluated in mice bearing SW620 xenografts. Excellent chemopotentiation and radiopotentiation were observed in vitro, with 17 of the compounds causing a greater temozolomide and topotecan sensitization than the benchmark inhibitor AG14361 and 10 compounds were more potent radiosensitizers than AG14361. In tumor-bearing mice, none of the compounds were toxic when given alone, and the antitumor activity of the PARP inhibitor-temozolomide combinations was unrelated to toxicity. Compounds that were more potent chemosensitizers in vivo than AG14361 were also more potent in vitro, validating in vitro assays as a prescreen. These studies have identified a compound, AG14447, as a PARP inhibitor with outstanding in vivo chemosensitization potency at tolerable doses, which is at least 10 times more potent than the initial lead, AG14361. The phosphate salt of AG14447 (AG014699), which has improved aqueous solubility, has been selected for clinical trial.

Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial.

BACKGROUND: Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. METHODS: In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1.0-1.85 mmol/L or 1.25-2.5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with , number . FINDINGS: Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference -7 to 14; p=0.70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI -10.5 to -2; p=0.007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. INTERPRETATION: Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

An evaluation of thymidine phosphorylase as a means of preventing thymidine rescue from the thymidylate synthase inhibitor raltitrexed.

The antitumour effect of thymidylate synthase inhibitors such as raltitrexed (RTX) may be reversed by salvage of thymidine (Thd). Since thymidine phosphorylase (TP) depletes Thd, the potential for tumour-selective depletion of Thd using antibody-mediated delivery of TP to tumours was investigated. In vitro studies demonstrated that 25 x 10(-3) units/ml TP depleted extracellular Thd (3 microM) and restored sensitivity to the growth inhibitory effects of RTX in Lovo and HT29 cell lines. Thymidine concentrations in xenograft tumours were inversely proportional to the activity of TP in the tumour, and the presence of a subcutaneous Lovo xenograft reduced plasma Thd concentrations from 0.92 +/- 0.07 to 0.37 +/- 0.04 microM. Intravenous administration of native TP enzyme depleted plasma Thd to 5 nM, but following rapid elimination of TP, plasma Thd returned to pretreatment values. There was no effect on tumour TP or Thd. Conjugation of TP to the A5B7 F(ab)2 antibody fragment, which targets carcinoembryonic antigen (CEA) expressed on colorectal cell-lines such as Lovo, did result in selective accumulation of TP in the tumour. However, there was no tumour-selective depletion of Thd and there did not appear to be any potential benefit of combining antibody-targeted TP with RTX.

Chiropractic manipulation affects the difference between arterial systolic blood pressures on the left and right in normotensive subjects.

OBJECTIVE: The purpose of this study is to determine whether chiropractic manipulation is associated with any measurable changes in the difference between the arterial blood pressures on the left and right before and after treatment in normotensive subjects. METHODS: A nonrandomized, matched pair, controlled clinical trial, with the treatment (manipulation) group and control (resting) group matched for age and sex, was performed in chiropractic student clinics in London, UK. The treatment group consisted of 35 new patients presenting to a single student chiropractor between the start of April 2003 and the end of August 2003. The control group consisted of 35 nonpatients matched for sex and age. The intervention was chiropractic manipulation. Preintervention and postintervention systolic and diastolic blood pressures were recorded in both arms through the use of a digital oscillometric sphygmomanometer. RESULTS: A significant difference was found between the pre- and posttreatment blood pressure differences for systolic pressures (P = .01), but no significant difference was found in either set of control data or the treatment diastolic values. A significant difference was also found between the treatment and control group's preintervention systolic differences (P = .002), but not between the groups at any other time. CONCLUSION: Chiropractic treatment appears to have an effect on the difference in systolic blood pressure between the arms, which is not shown in the control group or the diastolic treatment group values. This may be attributable to a difference between the 2 groups' preintervention systolic values; however, there was no significant difference between the 2 groups after intervention.