Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The “treasure trove” of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono- or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

/pdf/overcoming-cancer-therapeutic-bottleneck-by-drug-repurposing-26m168lv8z.pdf

Overcoming cancer therapeutic bottleneck by drug repurposing

Inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, creating a Dr. Jekyll or Mr. Hyde conundrum when examining mechanisms of action. This is due to tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. Tumor infiltration by macrophages is generally associated with neoangiogenesis and negative outcomes, whereas dendritic cell (DC) infiltration is typically associated with a positive clinical outcome in association with their ability to present tumor antigens (Ags) and induce Ag-specific T cell responses. Myeloid-derived suppressor cells (MDSCs) also infiltrate tumors, inhibiting immune responses and facilitating tumor growth and metastasis. In contrast, T cell infiltration of tumors provides a positive prognostic surrogate, although subset analyses suggest that not all infiltrating T cells predict a positive outcome. In general, infiltration by CD8+ T cells predicts a positive outcome, while CD4+ cells predict a negative outcome. Therefore, the analysis of cellular phenotypes and potentially spatial distribution of infiltrating cells are critical for an accurate assessment of outcome. Similarly, cellular infiltration of metastatic foci is also a critical parameter for inducing therapeutic responses, as well as establishing tumor dormancy. Current strategies for cellular, gene, and molecular therapies are focused on the manipulation of infiltrating cellular populations. Within this review, we discuss the role of tumor infiltrating, myeloid-monocytic cells, and T lymphocytes, as well as their potential for tumor control, immunosuppression, and facilitation of metastasis.

Inflammatory cell infiltration of tumors : Jekyll or Hyde

Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma

Dizziness accounts for an estimated 5 percent of primary care clinic visits The patient history can generally classify dizziness into one of four categories: vertigo, disequilibrium, presyncope, or lightheadedness The main causes of vertigo are benign paroxysmal positional vertigo, Meniere disease, vestibular neuritis, and labyrinthitis Many medications can cause presyncope, and regimens should be assessed in patients with this type of dizziness Parkinson disease and diabetic neuropathy should be considered with the diagnosis of disequilibrium Psychiatric disorders, such as depression, anxiety, and hyperventilation syndrome, can cause vague lightheadedness The differential diagnosis of dizziness can be narrowed with easy-to-perform physical examination tests, including evaluation for nystagmus, the Dix-Hallpike maneuver, and orthostatic blood pressure testing Laboratory testing and radiography play little role in diagnosis A final diagnosis is not obtained in about 20 percent of cases Treatment of vertigo includes the Epley maneuver (canalith repositioning) and vestibular rehabilitation for benign paroxysmal positional vertigo, intratympanic dexamethasone or gentamicin for Meniere disease, and steroids for vestibular neuritis Orthostatic hypotension that causes presyncope can be treated with alpha agonists, mineralocorticoids, or lifestyle changes Disequilibrium and lightheadedness can be alleviated by treating the underlying cause

Dizziness: a diagnostic approach.

Aims: Hearing loss is a common disability that has a profound impact on communication and daily functioning in the elderly. The present study assesses the effects of hearing aids on mood, quality of life and caregiver burden when hearing loss, comorbidity and depressive symptoms coexist in the elderly.

Methods:  A total of 15 patients aged older than 70 years suffering from hearing loss and depressive mood were recruited. Comorbidity was evaluated by the Cumulative Illness Rating Scale, functional ability by the Activities of Daily Living scale and the Lawton Instrumental Activities of Daily Living scale, cognitive capacity by the Mini-mental State Examination and the Clock Drawing Test, psychological status by the Center for Epidemiological Studies-Depression scale, and quality of life by the Short Form (36) Health Survey. Caregiver burden was appraised by the Caregiver Burden Inventory. Testing was carried out at baseline and at 1-, 3- and 6-month intervals, assessing the use of binaural digital and programmable hearing aids.

Results:  Reduction in depressive symptoms and improved quality of life at statistically significant levels were observed early on with the use of hearing aids. In particular, general health (P < 0.02), vitality (P < 0.03), social functioning (P < 0.05), emotional stability (P < 0.05) and mental health (P < 0.03) all changed for the better, and were maintained for the study duration. The degree of caregiver burden also declined, remaining low throughout the study.

Conclusions:  The benefits of digital hearing aids in relation to depressive symptoms, general health and social interactivity, but also in the caregiver – patient relationship, were clearly shown in the study. The elderly without cognitive decline and no substantial functional deficits should be encouraged to use hearing aids to improve their quality of life. Geriatr Gerontol Int 2012; 12: 440–445.

Hearing loss and depressive symptoms in elderly patients

Purpose To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins. Patients and Methods Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular in...

Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial

The objective of this study was to determine the reliability and validity of the Hungarian version of the original Tinnitus Handicap Inventory (THI). In the study design the original THI (THI-US) was translated into Hungarian by three independent investigators. The final Hungarian version (THI-HUN) was constructed on the basis of these Hungarian interpretations and then administered to 72 patients suffering from chronic tinnitus. Construct validity was assessed using short version of Beck's Depression Inventory (BDI), Perceived Stress Scale (PSS4 version), Visual Analogue Scale (VAS) (loudness, annoyance and pitch of tinnitus), pure tone audiometry and tinnitometry. The 72 participants were 43 women and 29 men. Their mean age was 49.86 years with a mean tinnitus duration of 4.16 years. In the results THI-HUN and its subscales showed good internal consistency reliabilities (α = 0.95-0.74), with significant correlation between THI-HUN total score and subscales and the BDI, PSS4 and VAS annoyance. There was a high or moderate correlation between THI-HUN total score and VAS loudness, tinnitus duration, hearing loss and subjective perception of tinnitus loudness. The VAS pitch of tinnitus, the subjective perception of tinnitus pitch, age, gender and level of education did not show any correlation with THI-HUN total score. The test-retest reliability was high (r = 0.97). We conclude that a valid and reliable THI-HUN questionnaire was constructed.

Hungarian adaptation of the Tinnitus Handicap Inventory: reliability and validity

Depression is a state of depressed mood characterized by feelings of sadness, despair, and discouragement. Depression ranges from normal feelings of "the blues" through dysthymia to major depression. Endogenous depression has been identified with a specific symptom complex: psychomotor retardation, early morning awakening, weight loss, excessive guilt, and lack of reactivity to the environment. Reactive depression is precipitated by a stressfullife event. In the field of depression, we found an overlapping activity between psychiatry and neurootology. Our sample comprises 134 patients (53 [39.55%] male, 81 [60.45%] female) who were classified either by psychiatrists or by neurologists as suffering from depression. By evaluating our neurootological history data bank (Neurootological Data Evaluation-Claussen [NODEC]) as regards 6 important vertigo symptoms, we found that patients presented with a frequency of 2.10 signs per patient. When we extended the list to 11 vertigo and nausea signs, we found 2.93 signs per patients. All patients underwent an objective and quantitative neurootometric analysis. The following rates of abnormal findings were observed: butterfly calorigram of polygraphic electronystagmography, 69.40%; stepping craniocorpograms, 69.40%; and bone-conduction pure-tone audiometry of the right ear, 28.36%, and of the left ear, 36.57%.

/pdf/depressive-disorders-in-relation-to-neurootological-1ny7ngrszr.pdf

Depressive disorders in relation to neurootological complaints.

Pathologies from childhood to adolescence carry physical, cognitive, motor, linguistic, perceptual, social, emotional, and neurosensory characteristics. The ages between 8 and 14 or 15 especially carry very special traits of a rollover in data processing with respect to balance regulation. Data acquisition of neurootological function provides us with a network of information about the sensory status of our young patients. Major neurootological complaints leading to functional neurootological investigations are vertigo (including giddiness), dizziness, and nausea. These complaints may occur acutely but also are present in some patients at a young age as longer-lasting complaints. Physiological and clinical vertigo syndromes are commonly found as a combination of four principal phenomena: perceptual (vertigo), oculomotor (nystagmus), postural (dystaxia), and vegetative (nausea, vomiting). These four cardinal manifestations of vertigo are related to different levels of the vestibular analyzer and require different methods of investigation. The focus of our study is the phase of restructuring of equilibrium regulation in children between the ages of 8 and 15 years.

/pdf/neurootological-aspects-of-juvenile-vertigo-4wht0k8cpx.pdf

Neurootological aspects of juvenile vertigo.

Acoustic CR®-neuromodulation first experiencies in Hungary in novel patented method in therapy of chronic subjectiv tiinitus

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