Therapeutic and preventive properties of honey and its bioactive compounds in cancer: an evidence-based review.

Despite the much improved therapeutic approaches for cancer treatment that have been developed over the past 50 years, cancer remains a major cause of mortality globally. Considerable epidemiological and experimental evidence has demonstrated an association between ingestion of food and nutrients with either an increased risk for cancer or its prevention. There is rising interest in exploring agents derived from natural products for chemoprevention or for therapeutic purposes. Honey is rich in nutritional and non-nutritional bioactive compounds, as well as in natural antioxidants, and its potential beneficial function in human health is becoming more evident. A large number of studies have addressed the anti-cancer effects of different types of honey and their phenolic compounds using in vitro and in vivo cancer models. The reported findings affirm that honey is an agent able to modulate oxidative stress and has anti-proliferative, pro-apoptotic, anti-inflammatory, immune-modulatory and anti-metastatic properties. However, despite its reported anti-cancer activities, very few clinical studies have been undertaken. In the present review, we summarise the findings from different experimental approaches, including in vitro cell cultures, preclinical animal models and clinical studies, and provide an overview of the bioactive profile and bioavailability of the most commonly studied honey types, with special emphasis on the chemopreventive and therapeutic properties of honey and its major phenolic compounds in cancer. The implications of these findings as well as the future prospects of utilising honey to fight cancer will be discussed.

Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor.

Aberrantly high levels of tyrosine-phosphorylated signal transducer and activator of transcription 3 (p-STAT3) are found constitutively in ~50% of human lung and breast cancers, acting as an oncogenic transcription factor. We previously demonstrated that Manuka honey (MH) inhibits p-STAT3 in breast cancer cells, but the exact mechanism remained unknown. Herein, we show that MH-mediated inhibition of p-STAT3 in breast (MDA-MB-231) and lung (A549) cancer cell lines is accompanied by decreased levels of gp130 and p-JAK2, two upstream components of the IL-6 receptor (IL-6R) signaling pathway. Using an ELISA-based assay, we demonstrate that MH binds directly to IL-6Rα, significantly inhibiting (~60%) its binding to the IL-6 ligand. Importantly, no evidence of MH binding to two other cytokine receptors, IL-11Rα and IL-8R, was found. Moreover, MH did not alter the levels of tyrosine-phosphorylated or total Src family kinases, which are also constitutively activated in cancer cells, suggesting that signaling via other growth factor receptors is unaffected by MH. Binding of five major MH flavonoids (luteolin, quercetin, galangin, pinocembrin, and chrysin) was also tested, and all but pinocembrin could demonstrably bind IL-6Rα, partially (30-35%) blocking IL-6 binding at the highest concentration (50 µM) used. In agreement, each flavonoid inhibited p-STAT3 in a dose-dependent manner, with estimated IC50 values in the 3.5-70 µM range. Finally, docking analysis confirmed the capacity of each flavonoid to bind in an energetically favorable configuration to IL-6Rα at a site predicted to interfere with ligand binding. Taken together, our findings identify IL-6Rα as a direct target of MH and its flavonoids, highlighting IL-6R blockade as a mechanism for the anti-tumor activity of MH, as well as a viable therapeutic target in IL-6-dependent cancers.

Intradural extramedullary primary hydatid cyst of the spine: a case report and review of literature.

Primary intradural extramedullary hydatid cyst is a rare form of parasitic infection, causing focal neurological signs, commonly observed in sheep-raising areas of the world. We report a rare case of intradural, extramedullary spinal cyst, which we had misdiagnosis in the first surgery, because of rarity of the case. A 55-year-old man presented to our hospital in August 2008. He was admitted to our clinic because of lumbar pain of increasing severity and progressive difficulty with walking and stiffness of both lower limbs, which had lasted for 1 month. On the basis of imaging results, arachnoid cyst of the lumbar spine was diagnosed. Due to rapid progression of the patient's symptoms toward spastic paraplegia, he underwent an emergency surgical decompression procedure. The patient underwent exploratory surgery using a posterior approach. A L1-L2 laminectomy was performed. After opening the dura, an intradural extramedullary cystic mass was determined. The surgical specimen measured 6 × 2 cm and was described as a whitish, pearl-like, semitranslucent, cystic material, which was thought to be parasitic. Surgery has to be followed by albendazole therapy.

A review of the tragal pointer: anatomy and its importance as a landmark in surgical procedures.

The tragal pointer has long been used as a surgical landmark for the identification of the facial nerve trunk and the maxillary artery in such procedures as parotidectomy, internal fixation of subcondylar and condylar fractures, mandibular osteotomy, temporomandibular joint arthroplasty, and percutaneous blocks of branches of the trigeminal nerve and pterygopalatine ganglion. Aside from its use as an external landmark, it has also been implicated as a contributor to crease formation in the presence of peripheral arterial disease. This article will review the available literature on the tragal pointer's use as an external landmark.

Correction: Jose et al. Transferrin-Conjugated Docetaxel-PLGA Nanoparticles for Tumor Targeting: Influence on MCF-7 Cell Cycle. Polymers 2019, 11, 1905.

In the original publication [...].

The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer.

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis.

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan's inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

An interrupted inferior vena cava in a situs inversus. Case report and review of the literature.

Situs inversus with interrupted inferior vena cava is an uncommon anatomic variant found in the abdominal and thoracic viscera. In this report, we present a 59-year-old woman with this variation, found during gross anatomical dissection. While this type of variation has been variable, in the present case the hepatic veins drained directly into a very short (2.2 cm) inferior vena cava. The infrarenal component of the inferior vena cava was present and drained into the azygos and hemiazygos veins. Clinical considerations of this variant anatomy are of interest, as they may present in patients as pathology on cross sectional imaging.

Anatomy of the reflected ligament of the inguinal region.

BACKGROUND: There is a paucity in the literature regarding the reflected ligament. Therefore, the present study was performed in order to further elucidate this anatomy. MATERIAL AND METHODS: Eighteen formalin-fixed adult cadavers (35 sides) underwent dissection of the medial inguinal region. The reflected ligament was observed for and when identified, its dimensions were measured. RESULTS: 83% of sides were found to have a reflected ligament. These were identified in 16 male and 13 female bodies. The size and shape for the reflected ligaments were variable but overall, triangular in nature. In general, the reflected ligament was found to extend from the lacunar and medial inguinal ligaments and extended obliquely toward the midline at an approximate 45 degrees angle to insert near the linea alba. Two ligaments (6.9 %) were identified that interdigitated with the contralateral reflected ligament. The medial and lateral lengths of the ligament had a mean measurement of 2.28 and 2.58 cm. The base of the reflected ligament had a mean of 2.52 cm and the height of this ligament was found to have a mean of 2.56 cm. The mean area of the reflected ligament was calculated as 2.93 cm(2). There was no statistically significant difference between right or left sides or between genders. CONCLUSIONS: The reflected ligament was identified in the majority of our specimens and this structure usually contributed to the formation of the posteromedial wall of the external inguinal ring. Therefore, this fact should be included in future descriptions of this ligament.

The costoclavicular ligament revisited: a functional and anatomical study.

INTRODUCTION: The sternoclavicular joint is of clinical importance. However, there is scant information in the literature regarding one ligament of this area, the costoclavicular ligament (CCL). MATERIAL AND METHODS: In order to further elucidate this structure, 10 adult formalin-fixed cadavers (17 sides) underwent dissection of the CCL. Once the CCL was identified, measurements were made of its dimensions and observations made of its anatomy. Next, ranges of motion were performed of the upper extremity and the CCL observed for tension or laxity. RESULTS: Of the 17 sternoclavicular regions examined 16 (94%) were found to possess a CCL. The average medial and lateral lengths, width and thickness were 1, 2, 1.2, 0.340 cm, respectively. The width of the CCL was statistically smaller in women that in men. The majority of ligaments were single structures traveling from the inferior surface of the medial clavicle just lateral and sometimes-fused (12.5%) to the lateral edge of the sternoclavicular joint. These fibers then terminated on the medial end of the first rib and first costal cartilage (75%) or exclusively onto the first costal cartilage (25%). Most ligaments were single and not composed of two parts. Arm abduction resulted in tautness of the ligament and increased as the degree of abduction increased. Internal rotation of the arm translated into medial shift of the clavicle, raising the clavicle away from the first rib creating tension on the CCL. Moderate degrees of external rotation were required before the CCL became taut and even began to pull the first rib laterally. Small amounts of protraction and retraction of the scapula both put the CCL under tension. CONCLUSIONS: The CCL is a constant structure found just lateral to the sternoclavicular joint. This ligament was a single band in the majority of our specimens and limited most ranges of motion of the proximal upper limb thus stabilizing the sternoclavicular region.

Transferrin-Conjugated Docetaxel-PLGA Nanoparticles for Tumor Targeting: Influence on MCF-7 Cell Cycle.

Targeted drug delivery systems are commonly used to improve the therapeutic index of anti-cancer drugs by increasing their selectivity and reducing systemic distribution and toxicity. Ligand-conjugated nanoparticles (NPs) can be effectively applied for active chemotherapeutic targeting to overexpressed receptors of tumor cells. In this study, transferrin (Tf) was successfully conjugated with poly-l-lactic-co-glycolic acid (PLGA) using ethylene diamine confirmed by NMR, for the loading of docetaxel trihydrate (DCT) into PLGA nanoparticles (NPs). The DCT-loaded Tf-conjugated PLGA NPs were produced by an emulsion-solvent evaporation technique, and a 32 full factorial design was used to optimize the nanoparticle formulations. The DCT-loaded Tf-conjugated PLGA NPs were characterized by FTIR spectroscopy, differential scanning calorimetry, powder X-ray diffraction (PXRD), TEM, particle size, and zeta potential analysis. In vitro release kinetics confirmed that release of DCT from the designed formulations followed a zero-order kinetics and a diffusion controlled non-Fickian release profile. The DCT-loaded Tf-conjugated PLGA NPs were evaluated in vitro in MCF-7 cells for bioactivity assessment. Cytotoxicity studies confirmed that the Tf-conjugated PLGA NPs were more active than the non-conjugated counterparts. Cell uptake studies re-confirmed the ligand-mediated active targeting of the formulated NPs. From the cell cycle analysis, the anti-cancer activity of DCT-loaded Tf-conjugated PLGA NPs was shown to occur by arresting the G2/M phase.

Postrenal transplant hemophagocytic lymphohistiocytosis and thrombotic microangiopathy associated with parvovirus b19 infection.

Persistent anemia is a known consequence of Parvovirus B19 (B19) infection following renal transplantation. However, to date, no description of B19-related hemophagocytic lymphohistiocytosis (HLH) exists in renal transplant recipients. We report a 24-year-old male kidney recipient, who presented with fever, severe anemia and allograft dysfunction two years following transplantation. Hyperferritinemia, hypertriglyceridemia, elevated serum lactate dehydrogenase, pancytopenia and fragmented red blood cells on the peripheral blood were also noted. Bone marrow examination revealed giant pronormoblasts and frequent histiocytes with intracellular hematopoietic elements, consistent with HLH. Renal allograft biopsy revealed closure of the lumen of glomerular capillaries and thickening of the capillary walls compatible with thrombotic microangiopathy. The presence of anti-B19 IgM antibody and viral DNA in the patient's serum (detected by real-time PCR) confirmed an acute B19 infection. Following high-dose intravenous immunoglobulin therapy, the anemia gradually resolved and renal function improved. As far as we know, this is the first report of B19-associated HLH and thrombotic microangiopathy in a renal transplant recipient.

Mucormycotic pseudoaneurysm of the common carotid artery with tracheal involvement.

Mucormycosis is an emerging and fatal fungal infection. A high index of suspicion and the knowledge of its potential manifestations are essential for early diagnosis. We describe a patient with acute lymphoblastic leukaemia (L2 subtype) who developed a neck mass following a course of induction chemotherapy. Doppler ultrasonography and angiography of the neck revealed a pseudoaneurysm of the right common carotid artery. The patient then developed haemoptysis. Surgical exploration revealed a necrotic right common carotid artery with anteromedial pseudoaneurysm and adjacent tracheal wall perforation. Local debridement and tracheal repair were performed. Nonseptate hypheal invasion (mucormycosis) was found on the microscopic examination of the excised arterial wall. A subsequent recurrence of pseudoaneurysm was treated with local surgical debridement and intravenous amphotericin B (Fungizone) administration. Although rare, clinicians should be aware of these possible presenting features of mucormycosis as early diagnosis and treatment may potentially improve the survival.

The clinical anatomy of the triangle of Grynfeltt.

Dorsal lumbar hernias are rare pathologies of the abdominal wall. Such hernias may manifest within the superior lumbar triangle of Grynfeltt (TG) or the triangle of Petit. The aim of our study was to identify and describe variations in the size and anatomy of the TG. The triangle was studied in 50 adult human cadavers, and dimensions and surface area were measured. The TG was identified in 82% of cases. Based on surface area parameters, we were able to classify the triangles into four distinct types. Type I (50%), or small triangles, had a surface area of <5 cm(2). Type II (22%, n=22) were defined as triangles intermediate in size with surface areas of 5-15 cm(2). Type III (10%, 10) were large triangles with surface areas of >15 cm(2). Finally, Type 0 (18%, 18) did not exhibit a triangle; instead, the aponeurosis of the transversus abdominis was enclosed by the external abdominal oblique muscle and the sacrospinalis muscle. We present these data with the hope that after further investigation in a clinical setting, they may serve practitioners in predicting which morphometric variations of the TG most predispose patients to posterior wall herniation.

Do mechanical fluid laws dictate the branching pattern of the renal artery?

INTRODUCTION: Anatomy of the renal artery is an important issue in the renal transplantation era. Multi-detector computed tomography angiography (MDCTA) is an accurate modality for the preoperative assessment of live renal donors, and it provides excellent details of donor arterial anatomy. We studied the relationship between the angle of emergence of the renal artery from the aorta and its branching pattern. METHODS: In this study, the MDCTA images obtained from the 138 kidneys of 77 potential renal transplant donors were studied. The courses of the right and left renal arteries from the aorta to the kidney hilus were delineated. The branching angle of the renal artery from the aorta (beta, angle) and the length of the renal artery from the aorta until its first division were measured (Delta, distance). The renal artery deviation from the perpendicular plane of the aorta (D, factor of deviation) was calculated by the following formula: D = (1 - sin [beta]). The cosine of this angle (cos [beta]) was also calculated. Statistical analyses were performed with Pearson correlation tests. The P value was set at .05. RESULTS: The mean age of patients was 28.7 +/- 4.3 with a male to female ratio of 63:14. The mean Delta distance and small de, Cyrillic diameter were 34.37 +/- 10.68 mm (range, 10-58) and 6.13 +/- 1.37 mm (range, 2.8-9.9), respectively. The mean beta angle, factor of deviation, and cos (beta) were 62.19 degrees +/- 16.44, 0.15 +/- 0.14, and 0.45 +/- 0.25, respectively. Significant negative correlations were found between the beta angle, and Delta distance (r = -0.308; P < .001), and small de, Cyrillic diameter (r = -0.303; P = .003). Factor of deviation and cos (beta) were directly associated Delta distance and small de, Cyrillic diameter. CONCLUSION: These findings indicated that with the main renal artery axis deviating from the perpendicular plane of the aorta or with a smaller branching angle, this artery had a greater diameter and underwent late branching. This study suggested that the renal artery diameter and branching pattern might be determined by the mechanical fluid laws.

Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection.

INTRODUCTION: During kidney transplantation, the first contact between the recipient's immune system and the donor organ takes place immediately following the arterial anastomosis. The aim of this study was to evaluate the efficacy of a single, low-dose anti-thymocyte globulin (ATG) prophylaxis in the reduction of early acute rejection in renal allograft recipients. METHODS: In a randomized, controlled clinical trial, we studied the rate of acute rejection within the first month of kidney transplantation in patients who had received their transplant at a single center between the years 2004 and 2007. The patients were divided into 2 groups: group 1 (n = 37) received cyclosporine, mycophenolate mofetil or azathioprine, and prednisolone; group 2 (n = 31) received the above-mentioned agents plus a single ATG bolus (Thymoglobulin; SangStat, Lyon, France; 4-5 mg/kg) the night before the transplantation ( approximately 12 hours before the operation). Blood urea and serum creatinine levels were measured regularly in the posttransplantation period. Acute allograft rejection was justified clinically and/or pathologically. Statistical analysis was performed by SPSS 13.0 using Student t test and Fisher exact test. A P value < or = .05 was considered to indicate statistical significance. RESULTS: There were no significant differences regarding the age and gender ratio between the 2 groups. Acute allograft rejection was found in 32.4% (n = 12) of group 1 patients, and was reduced to 12.9% (n = 4) in group 2 (P = .05). Hence, the first-month acute rejection episodes decreased by approximately 60% with ATG prophylaxis in renal transplant recipients. CONCLUSION: Prophylactic administration of a single and low-dose ATG the night before kidney transplantation could reduce the risk of acute allograft rejection in renal transplant recipients. However, further studies with a greater number of patients should be conducted to confirm these results.

Screening for renal artery stenosis in patients with aorticoiliac occlusive disease.

BACKGROUND: The prevalence of atherosclerotic renal artery disease has increased with improved life expectancy. Because renal artery stenosis is a potentially correctable cause of hypertension and ischemic nephropathy, early identification of this entity may lead to proper hypertension control and improved renal function and survival. The aim of this study was to determine the prevalence and patterns of subclinical renal artery stenosis in patients with aorticoiliac atherosclerosis. PATIENTS AND METHODS: The abdominal angiographies of 44 patients with high-grade aorticoiliac occlusive disease (> 70% stenosis) were reviewed for evidence of renal artery stenosis. This was compared to a group of 20 patients with mild-to-moderate aorticoiliac disease (< 70% stenosis). These patients had no history of renal artery disease or renal failure. RESULTS: In patients with high-grade aorticoiliac occlusive disease, renal artery stenosis was found in 25 patients (56.8%); 13 with unilateral (29.5%) and 12 (27.3%) with bilateral involvement. A hemodynamically significant stenosis (> 50%) was found in 11 patients (25%), one of whom had bilateral stenosis (2.3%). High-grade renal artery stenosis (> 70%) or complete arterial occlusion was noted on seven sides (7.9%). The most common sites of stenosis were the origin and first centimeter of the renal artery. In patients with mild-to-moderate aorticoiliac disease, renal artery stenosis was found in two patients (10%). CONCLUSIONS: The present study revealed that subclinical renal artery disease may be present in more than half of the patients with high-grade aorticoiliac atherosclerosis highlighting the need for proper risk stratifications and screening programs. Based on our results, we suggest that examination of the renal arteries in these patients may be necessary in order to delay or prevent complications. Additionally, such information may have important therapeutic implications in planning reconstructive vascular surgeries or percutaneous angioplasties.

Levator claviculae: a case report and review of the literature.

The levator claviculae is an uncommon anatomical variant found in the posterior cervical triangle. In this report we present a 78-year-old man with this muscular variation, which was found during gross anatomical dissection. While sites of insertion and origin have been variable, in the present case the muscle originated from the left transverse processes of C3 and C4, and inserted onto the lateral third of the ipsilateral clavicle. Clinical considerations of this variant anatomy are of interest, as they may present in patients as a supraclavicular mass and may also mimic pathology on cross-sectional imaging.

The ansa subclavia: a review of the literature.

The ansa subclavia, subclavian loop, Vieussens' ansa or Vieussens' loop is a nerve cord that connects the middle cervical and inferior cervical sympathetic ganglia, forming a loop around the subclavian artery. The structure of the ansa subclavia is evolutionarily conserved from rats, guinea pigs, the porcine species and dogs to humans. A common application in physiological studies is to electrically stimulate the ansa subclavia in animal models as a robust protocol to modulate stimulatory cardiac sympathetic input. Despite a large number of physiological studies utilizing the ansa subclavia, only very brief descriptions have been devoted to it in standard anatomy texts. An extensive search found only one report in the English language literature concerning the anatomy of the ansa subclavia. The aim of this report, therefore, was to provide a comprehensive review of the clinical anatomy of the ansa subclavia and to discuss its potential physiological functions.

Screening for thoracoabdominal aortic aneurysms in patients with aortoiliac atherosclerosis: a preliminary study.

Thoracoabdominal aortic aneurysms (TAAs) usually present with rupture and carry a high morbidity and mortality rate. Early detection of TAAs with screening methods and elective surgical repair could potentially diminish these complications. The present study was aimed at screening for TAA in patients with angiography-proven aortoiliac atherosclerosis (n=43). A group of patients without aortoiliac atherosclerosis was used as controls (n=15). Age, sex and aortic diameter at the level of the T12 vertebra were recorded. The subjects were divided into two age categories, the first made up of those aged less than 65 years and the second those aged 65 years or more. A T12 aortic diameter greater than 35 mm was used to indicate TAA. Statistical analyses were performed by independent t-test and general linear model with age category, sex and atherosclerosis as factors. The mean T12 aortic diameters were greater in patients with atherosclerosis than in the control group (25.2+/-5.0 vs. 22.9+/-2.4 mm; p=0.034). Two out of 43 patients (4.7%) with aortoiliac atherosclerosis had TAA, while no one in the control group had TAA. A general linear model showed that the interaction of age category and sex significantly affected the T12 aortic diameter [F (1.49)=4.044, p=0.050]. Post hoc (LSD) tests revealed that male patients aged over 65 had greater T12 aortic diameters than other patients. We conclude that patients with aortoiliac atherosclerosis may be at greater risk for developing TAA. Ageing and male sex may also be associated with thoracoabdominal aortic enlargement.