Marjorie R. Jenkins

Nanotechnology and human health: risks and benefits

Nanotechnology is expected to be promising in many fields of medical applications, mainly in cancer treatment. While a large number of very attractive exploitations open up for the clinics, regulatory agencies are very careful in admitting new nanomaterials for human use because of their potential toxicity. The very active research on new nanomaterials that are potentially useful in medicine has not been counterbalanced by an adequate knowledge of their pharmacokinetics and toxicity. The different nanocarriers used to transport and release the active molecules to the target tissues should be treated as additives, with potential side effects of themselves or by virtue of their dissolution or aggregation inside the body. Only recently has a systematic classification of nanomaterials been proposed, posing the basis for dedicated modeling at the nanoscale level. The use of in silico methods, such as nano‐QSAR and PSAR, while highly desirable to expedite and rationalize the following stages of toxicological research, are not an alternative, but an introduction to mandatory experimental work. Copyright

Fruits and dietary phytochemicals in bone protection

Osteoporosis is a disease of bone characterized by loss of bone matrix and deterioration of bone microstructure that leads to an increased risk of fracture. Cross-sectional studies have shown a positive association between higher fruit intake and higher bone mineral density. In this review, we evaluated animal and cellular studies of dried plum and citrus and berry fruits and bioactive compounds including lycopene, phenolics, favonoids, resveratrol, phloridzin, and pectin derived from tomato, grapes, apples, and citrus fruits. In addition, human studies of dried plum and lycopene were reviewed. Animal studies strongly suggest that commonly consumed antioxidant-rich fruits have a pronounced effect on bone, as shown by higher bone mass, trabecular bone volume, number, and thickness, and lower trabecular separation through enhancing bone formation and suppressing bone resorption, resulting in greater bone strength. Such osteoprotective effects seem to be mediated via antioxidant or anti-inflammatory pathways and their downstream signaling mechanisms, leading to osteoblast mineralization and osteoclast inactivation. In future studies, randomized controlled trials are warranted to extend the bone-protective activity of fruits and their bioactive compounds. Mechanistic studies are needed to differentiate the roles of phytochemicals and other constitutes in bone protection offered by the fruits. Advanced imaging technology will determine the effective doses of phytochemicals and their metabolites in improving bone mass, microarchitecture integrity, and bone strength, which is a critical step in translating the benefits of fruit consumption on osteoporosis into clinical data.

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM.

AKAP‐4: a novel cancer testis antigen for multiple myeloma

Purpose Immunotherapy promises to be a more gentle and successful cancer treatment when compared with current standard treatments. Multiple myeloma (MM) is still a fatal hematologic malignancy that represents approximately 1% of all cancers and 2% of all cancer deaths. Approximately 50,000 Americans currently have MM. The research to discover new suitable cancer targets is needed to improve the effects of immunotherapy. The AKAP family9s protein provides an organizing center about which various protein kinases and phosphatases can be assembled to create solid-state signaling devices that can signal, be modulated, and be trafficked within the cell. A member of this family, AKAP-4, is the focus of our study. Human AKAP-4 is a structural protein of the sperm fibrous sheath that also functions to anchor protein kinase A to this structure via the regulatory subunit of the kinase, and seems to be involved in sperm motility. Our aim was to investigate the presence of AKAP-4 as a novel cancer testis antigen target in MM patients. Methods We evaluated the expression of AKAP-4 mRNA in a normal panel of tissues and in 15 MM patients either by PCR and immunocytochemistry. The normal control investigated tissues were kidney, ovary, skeletal muscle, mammary, brain, heart, colon, stomach, liver, lung, pancreas, spleen, trachea, and bone marrow. Summary The analysis of the mRNA expression of AKAP-4 showed that none of the normal tissues produced any positive band signals, whereas 6 of the 15 investigated patients (40%) showed a positive band signal. The immunohistochemical approach to the normal tissue panel showed no staining in any of the evaluated organs, except for the control, the testis. Five of the 15 MM investigated cases (33.3%) showed positive cytoplasmic staining. Conclusion To our knowledge, we established for the first time that AKAP-4 is expressed at the transcriptional level in MM cases, with a rate of 40%, whereas it is not expressed in normal tissues. Immunocytochemical data confirmed the PCR observations even if with a slightly lower percentage rate (33.3%). Since AKAP-4 has yet not been studied in MM, this is the first study that gives evidence of its aberrant expression in MM and suggests its use as possible novel cancer testis antigen target in MM.

Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms.

Bioflavonoids are of considerable interest to human health as these serve as antioxidant and anticancer agents. Although epidemiological and experimental studies suggest that luteolin, a natural bioflavonoid, exhibits chemopreventive properties, its effectiveness as an antiproliferative agent against multidrug resistant (MDR) cancers is unclear. Thus, we assessed the antiproliferative effects of luteolin and associated molecular mechanisms using two MDR cancer cell lines that express high levels of P‐glycoprotein and ABCG2. In this article, we demonstrate that luteolin induces apoptosis in P‐glycoprotein‐ and ABCG2‐expressing MDR cancer cells without affecting the transport functions of these drug transporters. Analysis of various proliferative signaling pathways indicated that luteolin‐induced apoptosis involves reactive oxygen species generation, DNA damage, activation of ATR → Chk2 → p53 signaling pathway, inhibition of NF‐kB signaling pathway, activation of p38 pathway and depletion of antiapoptotic proteins. Importantly, use of luteolin in these analyses also identified specific molecular characteristics of NCI‐ADR/RES and MCF‐7/MitoR cells that highlight their different tissue origins. These results suggest that luteolin possesses therapeutic potential to control the proliferation of MDR cancers without affecting the physiological function of drug transporters in the body tissues.

Cancer Testis Antigens: Novel Biomarkers and Targetable Proteins for Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death in women and the leading cause from gynecological malignancies. Despite the recently improved outcomes of new chemotherapeutical agents in the therapy of ovarian cancer and the increased 5-year survival rate, the mortality of this malignancy disease remains unchanged. Ovarian cancer therapy is often correlated to the stage of the tumor, but the first step is usually surgical treatment. Afterward, various courses of chemotherapy and radiation are suggested. Obviously, the higher the developmental stage of the tumor, the less the probability is in eradicating it surgically, especially in relation to metastasis. It is clear that an early diagnosis of ovarian cancer is important for the survival of these patients. In order to identify ovarian cancer patients in the early stages, a number of studies are focusing on a particular class of antigens called cancer testis antigens. These antigens display high expression in tumors of different histology, but are normally restricted to the testis and have low or no expression in normal tissues. The testes are an immunologically-privileged site due to the presence of tight junctions between adjacent Sertoli cells that constitute the blood-testis barrier, which prevents auto-immune reactions. In the past few years, some of these antigens were demonstrated to be very promising for the early diagnosis and development of vaccines for ovarian cancer. This review aims to underline the most reliable cancer testis antigens under investigation at this moment.

Embedding Concepts of Sex and Gender Health Differences into Medical Curricula

Sex, a biological variable, and gender, a cultural variable, define the individual and affect all aspects of disease prevention, development, diagnosis, progression, and treatment. Sex and gender are essential elements of individualized medicine. However, medical education rarely considers such topics beyond the physiology of reproduction. To reduce health care disparities and to provide optimal, cost-effective medical care for individuals, concepts of sex and gender health need to become embedded into education and training of health professionals. In September 2012, Mayo Clinic hosted a 2-day workshop bringing together leading experts from 13 U.S. schools of medicine and schools of public health, Health Resources and Services Administration Office of Womens Health (HRSA OWH), the National Institutes of Health (NIH) Office of Research on Womens Health (ORWH), and the Canadian Institute of Health and Gender. The purpose of this workshop was to articulate the need to integrate sex- and gender-based content into medical education and training, to identify gaps in current medical curricula, to consider strategies to embed concepts of sex and gender health into health professional curricula, and to identify existing resources to facilitate and implement change. This report summarizes these proceedings, recommendations, and action items from the workshop.

Cancer Testis Antigen Vaccination Affords Long-Term Protection in a Murine Model of Ovarian Cancer

Sperm protein (Sp17) is an attractive target for ovarian cancer (OC) vaccines because of its over-expression in primary as well as in metastatic lesions, at all stages of the disease. Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 cells, following prophylactic and therapeutic treatments. This is the first time that a mouse counterpart of a cancer testis antigen (Sp17) was shown to be expressed in an OC mouse model, and that vaccination against this antigen significantly controlled tumor growth. Our study shows that the CpG-adjuvated Sp17 vaccine overcomes the issue of immunologic tolerance, the major barrier to the development of effective immunotherapy for OC. Furthermore, this study provides a better understanding of OC biology by showing that Th-17 cells activation and contemporary immunosuppressive T-reg cells inhibition is required for vaccine efficacy. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.

Aging, cancer, and cancer vaccines.

World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people [1]. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 [2]. Further, cancer-related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older [3]. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression.

The differential impact of depressive symptom clusters on cognition in a rural multi‐ethnic cohort: a Project FRONTIER study

To examine the differential impact of depressive symptom clusters on neuropsychological functioning in a rural‐dwelling, multi‐ethnic cohort.