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Background: Aspirin (acetylsalicylic acid) and celecoxib have been used as potential anti-cancer therapies. Aspirin exerts its therapeutic effect in both cyclooxygenase (COX)-dependent and -independent pathways to reduce tumor growth and disable tumorigenesis. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces factors that cause inflammation and pain. The question is whether aspirin and celecoxib have other molecular targets of equal or more therapeutic efficacy with significant anti-cancer preventive benefits., Aim: Here, we propose that aspirin and celecoxib exert their anti-cancer effects by targeting and inhibiting mammalian neuraminidase-1 (Neu-1). Neu-1 has been reported to regulate the activation of several receptor tyrosine kinases (RTKs) and TOLL-like receptors and their downstream signaling pathways. Neu-1 in complex with matrix metalloproteinase-9 (MMP-9) and G protein-coupled receptors (GPCRs) has been reported to be tethered to RTKs at the ectodomain., Materials and Methods: The WST-1 cell viability assay, Caspase 3/7 assay, and Annexin V assay were used to evaluate the cell viability and detect apoptotic and necrotic cells following treatment in MiaPaCa-2, PANC-1 and the gemcitabine-resistant PANC-1 variant (PANC-1 GemR) cells. Microscopic imaging, lectin cytochemistry, and flow cytometry were used to detect levels of α-2,3 sialic acid. Epidermal growth factor (EGF)-stimulated live cell sialidase assays and neuraminidase assays were used to detect Neu-1 activity. Immunocytochemistry was used to detect levels of EGFR and phosphorylated EGFR (pEGFR) following treatment., Results: For the first time, aspirin and celecoxib were shown to significantly inhibit Neu-1 sialidase activity in a dose- and time-dependent manner following stimulation with EGF. Aspirin blocked Neu-1 desialylation of α-2,3-sialic acid expression following 30 min stimulation with EGF. Aspirin and celecoxib significantly and dose-dependently inhibited isolated neuraminidase ( Clostridium perfringens ) activity on fluorogenic substrate 2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (4-MUNANA). Aspirin inhibited phosphorylation of the EGFR in EGF-stimulated cells. Aspirin dose- and time-dependently induced CellEvent caspase-3/7 + cells as well as apoptosis and necrosis on PANC-1 cells., Conclusion: These findings signify a novel multimodality mechanism(s) of action for aspirin and celecoxib, specifically targeting and inhibiting Neu-1 activity, regulating EGF-induced growth receptor activation and inducing apoptosis and necrosis in a dose- and time-dependent manner. Repurposing aspirin and celecoxib as anti-cancer agents may also upend other critical targets involved in multistage tumorigenesis regulated by mammalian neuraminidase-1., Significance: These findings may be the missing link connecting the anti-cancer efficacy of NSAIDs to the role of glycosylation in inflammation and tumorigenesis., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Qorri et al.)

Introduction: Targeted multimodal approaches need to be strategically developed to control tumour growth and prevent metastatic burden successfully. Breast cancer presents a unique clinical problem because of the variety of cellular subtypes that arise. The tumour stage and cellular subtypes often dictate the appropriate clinical treatment regimen. Also, the development of chemoresistance is a common clinical challenge with breast cancer. Higher doses and additional drug agents can produce additional adverse effects leading to a more aggressive malignancy. Acetylsalicylic acid (ASA), metformin (Met), and oseltamivir phosphate (OP) were investigated for their efficacy to sensitize MDA-MB-231 triple-negative breast cancer and its tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR) together in combination with Tmx treatment., Methods: Microscopic imaging, the formation of 3D multicellular tumour spheroids, immunocytochemistry, flow cytometry, Annexin V Assay, Caspase 3/7 Apoptosis Assay, tube formation assay and analysis, and WST-1 cell viability assay evaluated the formation of MCTS, morphologic changes, cell viability, apoptosis activity and the expression levels of ALDH1A1, CD44 and CD24 on the cell surface, MDA-MB231 triple-negative breast cancer, tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR)., Results: The results using a triple combination of ASA, Met and OP on MDA-MB-231 and MDA-MB-231-TmxR cells and their matrix-free 3D multicellular tumour spheroids (MCTS) formed by using the cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP)) peptide method demonstrate a consistent and significant decrease in cell and tumour spheroid viability and volume with increased apoptotic activity, and increased sensitivity to Tmx therapy. Tmx treatment of MDA-MB-231 cells in combination with ASA, Met and OP markedly reduced the CD44/CD24 ratio by 6.5-fold compared to the untreated control group. Tmx treatment of MDA-MB-231-TmxR cells in combination with ASA, Met and OP markedly reduced the ALDH1A1 by 134-fold compared to the same treatment for the parental cell line. Also, the triple combination treatment of ASA, Met, and OP inhibited vasculogenic endothelial cell tube formation and induced endothelial cell apoptosis., Conclusion: For the first time, the findings demonstrate that repurposing ASA, Met, and OP provides a novel and promising targeted multimodal approach in the treatment of triple-negative breast cancer and its chemoresistant variant., Competing Interests: Dr William Harless reports funding from ACOA/NRC and is employed by Encyt Technologies, Inc.. Sergey V Burov is employed by the Laboratory of Novel Peptide Therapeutics, Cytomed J.S.Co.. The authors have no other possible conflicts of interest in this work., (© 2020 Sambi et al.)

Metastatic breast cancer is the most common cancer in women after skin cancer, with a 5-year survival rate of 26%. Due to its high prevalence, it is important to develop therapies that go beyond those that just provide palliation of symptoms. Currently, there are several types of therapies available to help treat breast cancer including: hormone therapy, immunotherapy, and chemotherapy, with each one depending on both the location of metastases and morphological characteristics. Although technological and scientific advancements continue to pave the way for improved therapies that adopt a targeted and personalized approach, the fact remains that the outcomes of current first-line therapies have not significantly improved over the last decade. In this chapter, we review the current understanding of the pathology of metastatic breast cancer before thoroughly discussing local and systemic therapies that are administered to patients diagnosed with metastatic breast cancer. In addition, our review will also elaborate on the genetic profile that is characteristic of breast cancer as well as the local tumor microenvironment that shapes and promotes tumor growth and cancer progression. Lastly, we will present promising novel therapies being developed for the treatment of this disease.

One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation., Competing Interests: Disclosure M Sambi is a recipient of the Queen’s Graduate Award (QGA). S Haq is the recipient of QGA and the 2016 Ontario Graduate Scholarship (OGS). F Haxho was the recipient of the QGA, the Graduate Entrance Tuition Award (GETA), the Natural Sciences and Engineering Research Council of Canada (NSERC) Alexander Graham Bell Canada Graduate Scholarship-Master’s (CGS M), and now the Vanier Canada Graduate Scholarship. V Samuel is the recipient of the Queen’s University Principal’s Scholarship and the Board of Governor’s Award. The authors report no other conflicts of interest in this work.

Objective: To assess the potential benefit of virtual dialogues with experts as a method for educating family members and caregivers of patients with an acquired brain injury (ABI)., Methods: Knowledge of ABI was assessed by questionnaire for eight participants prior to and after interacting with a virtual dialogue method, called Virtual Conversations®. Participants also completed a survey regarding their perceived value of the experience., Results: Significant improvement on the Knowledge Questionnaire was apparent from before to after participation in the virtual dialogue by the Wilcoxon Signed-Rank Test (Z = -1.9734; p < 0.05). Five of eight participants showed large improvement on this test. All reported enjoying and learning from the experience., Conclusion: The virtual dialogue method increases knowledge of brain injury for most family caregivers. It is an effective and efficient way for family and friends of patients with ABI to learn about ABI in a short period of time at their own pace. Further evaluation of this method is indicated.

BACKGROUND: Some primary care physicians provide less than optimal care for depression (Kessler et al., Journal of the American Medical Association 291, 2581-90, 2004). However, the literature is not unanimous on the best method to use in order to investigate this variation in care. To capture variations in physician behaviour and decision making in primary care settings, 32 interactive CD-ROM vignettes were constructed and tested. AIM AND METHOD: The primary aim of this methods-focused paper was to review the extent to which our study method - an interactive CD-ROM patient vignette methodology - was effective in capturing variation in physician behaviour. Specifically, we examined the following questions: (a) Did the interactive CD-ROM technology work? (b) Did we create believable virtual patients? (c) Did the research protocol enable interviews (data collection) to be completed as planned? (d) To what extent was the targeted study sample size achieved? and (e) Did the study interview protocol generate valid and reliable quantitative data and rich, credible qualitative data? FINDINGS: Among a sample of 404 randomly selected primary care physicians, our voice-activated interactive methodology appeared to be effective. Specifically, our methodology - combining interactive virtual patient vignette technology, experimental design, and expansive open-ended interview protocol - generated valid explanations for variations in primary care physician practice patterns related to depression care.

The most common adult primary brain tumor is glioblastoma multiforme (GBM). Current treatment is surgical resection, adjuvant radiation and chemotherapy, which can extend the median survival 20-36 weeks (Mansky et al. Central nervous system tumors. In Abraham J, Allegra CJ, Gulley J, eds. Bethesda Handbook of clinical oncology, 2nd edn. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2000: 440-2; Knox S. Intracranial tumors. In Pillot G, Chantler M, Magiera H, Peles S, et al., eds. The Washington Manual Hematology and Oncology Subspecialty Consult. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2004: 204-6.). But treatment efficacy is limited, mandating the exploration of more effective treatments. We report on a patient with GBM treated as per a clinical protocol with high-dose methotrexate (12 g/m(2)), who expired within hours after the initiation of treatment secondary to transtentorial herniation. Although it is not completely clear what caused the patient's herniation, we think that high-dose methotrexate therapy may have played a crucial role. We suggest that high-dose methotrexate should be used cautiously in patients with GBM.

Copper deficiency is rarely reported as a cause of neutropenia and anemia through mechanisms not clearly understood. Most cases have been found in malnourished infants or persons receiving total parenteral nutrition without adequate copper. We report on two otherwise healthy young adults with severe neutropenia and anemia secondary to copper deficiency of unclear etiology, which quickly resolved after supplementation with copper gluconate. Both women consumed excessive quantities of soft drinks, which may have contributed to the development of their copper deficiency. Two cases of an unexplained copper deficiency anemia and neutropenia in otherwise healthy young adults found at a single institution over a short period of time suggests that this problem may be more widespread than is currently realized.

Over the last decade clinical trials have established the effectiveness of adjuvant chemotherapy in eradicating micrometastases in many different cancers, including breast, colon, and lung. This success stands in sharp contrast to our failure to cure clinically evident metastatic cancer. These dramatic polarities illustrate the critical importance of treatment timing if residual cancer is to be eradicated. Adjuvant chemotherapy is started only after recovery from surgery, a period of time that can exceed 30 days. During this time any cancer that remains after surgery will continue to divide. Although adjuvant chemotherapy has proven effective despite this time delay, there are reasons, both conceptual and quantitative, to think that its effectiveness could be magnified by a more prompt administration. The extent of this magnification is mathematically modeled in this paper. Surgery and the process of wound healing after surgery create a very favorable environment for the growth of the metastatic clone. Surgery can increase the number of circulating tumor cells and induce an immunosuppressive effect that might facilitate metastatic spread. And the process of wound healing can stimulate growth factors that have been shown to accelerate tumor cell growth. This situation is a double-edged sword. Although the metastatic clone should proliferate rapidly during this time, it should also, at least theoretically, be more sensitive to the effects of chemotherapy as more cells are pushed into a cycling phase. We derive a mathematical model based upon empirical data predicting that the effectiveness of a given chemotherapeutic regimen is inversely proportional to the tumor burden that has to be eradicated, which, in turn, is a function of when chemotherapy is started after surgery. Although the critical importance of timing in the treatment of cancer is intuitive, this knowledge has not yet been fully translated into the clinical practice of medical oncology. If the model presented is accurate, many people are dying unnecessarily of their cancer today because we are waiting too long after surgery to use highly effective chemotherapies, following well-trod clinical paths and established paradigms for how cancer should be treated.

Purpose: Although previous studies have examined race and sex differences in health care, few studies have investigated the possible role of physician bias. We evaluated the influence of race and sex on medical students' perceptions of patients' symptoms to determine if there are differences in these perceptions early in medical training., Subjects and Methods: One-hundred sixty-four medical students were randomly assigned to view a video of a black female or white male actor portraying patients with identical symptoms of angina. We evaluated students' perceptions of the actors' health state (based on their assessment of quality of life) using a visual analog scale and a standard rating technique, as well as the type of chest pain diagnosis., Results: Students assigned a lower value (indicating a less desirable health state) to the black woman than to the white man with identical symptoms [visual scale (mean +/- SD): 72 +/- 13 vs 67 +/- 12, P <0.02; standard gamble: 87 +/- 10 vs 80 +/- 15, P < 0.001). Nonminority students reported higher mean values for the white male patient (standard gamble: 89 +/- 8 vs 81 +/- 14 for the black female patient), whereas minority students' assessments did not differ by patient. Male students assigned a slightly lower value to the black female patient (standard gamble: 76 +/- 16 vs 87 +/- 10 for the white male patient). Students were less likely to characterize the black female patient's symptoms as angina (46% vs 74% for the white male patient, P = 0.001)., Conclusions: The way that medical students perceive patient symptoms appears to be affected by nonmedical factors.

Background: Epidemiologic studies have reported differences in the use of cardiovascular procedures according to the race and sex of the patient. Whether the differences stem from differences in the recommendations of physicians remains uncertain., Methods: We developed a computerized survey instrument to assess physicians' recommendations for managing chest pain. Actors portrayed patients with particular characteristics in scripted interviews about their symptoms. A total of 720 physicians at two national meetings of organizations of primary care physicians participated in the survey. Each physician viewed a recorded interview and was given other data about a hypothetical patient. He or she then made recommendations about that patient's care. We used multivariate logistic-regression analysis to assess the effects of the race and sex of the patients on treatment recommendations, while controlling for the physicians' assessment of the probability of coronary artery disease as well as for the age of the patient, the level of coronary risk, the type of chest pain, and the results of an exercise stress test., Results: The physicians' mean (+/-SD) estimates of the probability of coronary artery disease were lower for women (probability, 64.1+/-19.3 percent, vs. 69.2+/-18.2 percent for men; P<0.001), younger patients (63.8+/-19.5 percent for patients who were 55 years old, vs. 69.5+/-17.9 percent for patients who were 70 years old; P<0.001), and patients with nonanginal pain (58.3+/-19.0 percent, vs. 64.4+/-18.3 percent for patients with possible angina and 77.1+/-14.0 percent for those with definite angina; P=0.001). Logistic-regression analysis indicated that women (odds ratio, 0.60; 95 percent confidence interval, 0.4 to 0.9; P=0.02) and blacks (odds ratio, 0.60; 95 percent confidence interval, 0.4 to 0.9; P=0.02) were less likely to be referred for cardiac catheterization than men and whites, respectively. Analysis of race-sex interactions showed that black women were significantly less likely to be referred for catheterization than white men (odds ratio, 0.4; 95 percent confidence interval, 0.2 to 0.7; P=0.004)., Conclusions: Our findings suggest that the race and sex of a patient independently influence how physicians manage chest pain.

Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA(A) and GABA(B) agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA(B) receptors, but not GABA(A) receptors, in development of sensitization to the locomotor stimulant effects of ethanol.

Immunization with cocaine-keyhole limpet hemocyanin (KLH) conjugate elicited the formation of anti-cocaine antibody sufficient to blunt the effects of cocaine in rats. Cocaine was bound to KLH for immunization with the photoactivatable crosslinker N-hydroxysuccinimide-4-azidobezoate (HSAB). Immunization with the cocaine-KLH-complete Freund's adjuvant complex was effective in attenuating the analgesic and reinforcing effects of cocaine in laboratory rats. Enzyme-linked dot blot assay revealed the presence of anti-cocaine antibody in serum. Competitive binding studies suggest that the antibody was specific to cocaine. Active immunization for cocaine may provide an alternative to drug treatment and may provide protection from addiction.

The Technological Innovations in Medical Education (TIME) Project has created an interactive videodisc patient-simulation model that provides faculty with a new method for patient-centered teaching in the medical school classroom. The TIME model is designed to be controlled by a professor in the classroom setting, and incorporates voice recognition technology and video dramatization to create a believable patient encounter. Under the auspices of the Lister Hill National Center for Biomedical Communications, National Library of Medicine, where the Project originated in 1983, three medical schools participated in a field test of this "high-tech" model. Six faculty members made ten classroom presentations of two TIME simulations to 306 second-year medical students. The principal finding was that, in a group setting, a large majority of the students at all three schools became individually committed to the care and management of the simulated patient. They acted as if the patient's problems were real and left the session feeling as though they had interacted with an actual person. Therefore, in terms of simulating a real patient, the TIME patient-simulation model was validated, providing the basis for the development of new patient-centered methods to teach and test medical students in the classroom setting. The Project has been at the Georgetown University School of Medicine, where the model is being introduced into the existing curriculum, since 1988. It is currently being used as a part of the final examination for second-year students and in discussion-group settings for fourth-year students in the internal medicine clerkship. A field test is also under way using the TIME model to assess the clinical performance of third-year students.

Care in identifying the diaphragm on longitudinal sonograms through the liver allows differentiation of subpulmonic effusions from subphrenic fluid collections.

The instructional technology of voice recognition, interactive videodisc, and microcomputer offers new opportunities in medical education. The TIME Project is using this technology to create engaging, believable clinical situations that promote experiential learning, discovery learning, and contextual instruction in the medical school classroom. The TIME Project will conduct a field test of three interactive case studies as part of the introduction to clinical medicine curriculum at five medical schools to determine the educational effectiveness of the prototype design and its acceptance by faculty members and students.