Engineered nanomedicine for myeloma and bone microenvironment targeting

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.The incidence of bone metastasis is common in 60–80% of cancer patients (1). During bone metastasis, cancer cells induce a sequence of changes in the microenvironment such as secreting cytokines to increase the activity of osteoclasts via the parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL), and interleukin-6 (IL-6), resulting in increased bone resorption and secretion of growth factors from the bone matrix (2). This creates a “vicious cycle” of bone metastasis, where bone marrow becomes packed with cancer cells that develop resistance to conventional chemotherapy, and leads to devastating consequences of bone fractures, pain, hypercalcaemia, and spinal cord and nerve compression syndromes (2, 3). Multiple myeloma (MM) is a plasma cell cancer that proliferates primarily in bone marrow and causes osteolytic lesions (1). Antiresorption agents, such as bisphosphonates, may alleviate bone pain, but they are ineffective at inducing bone healing or osteogenesis in MM patients (4).Bortezomib is a proteasome inhibitor that has shown marked antitumor effects in patients with MM. Proteasome inhibitors, such as bortezomib, are also effective at increasing bone formation, both preclinically and clinically (5–9). However, the major drawback of bortezomib use in early stages of MM development is its toxicity, specifically, peripheral neuropathy (5). Therefore, we aimed to develop a method to deliver bortezomib with decreased off-target side effects by using bone-specific, bortezomib-loaded nanoparticles (NPs). The NP system was based on biodegradable, biocompatible, and Food and Drug Administration (FDA)-approved components, which are both clinically and translationally relevant. NPs derived from poly(d,l-lactic-co-glycolic acid) (PLGA), a controlled release polymer system, are an excellent choice because their safety in the clinic is well established (10, 11). Polyethylene glycol (PEG)-functionalized PLGA NPs are especially desirable as PEGylated polymeric NPs have significantly reduced systemic clearance compared with similar particles without PEG (12, 13). A number of FDA-approved drugs in clinical practice use PEG for improved pharmaceutical properties such as enhanced circulation in vivo (12, 13). To target NPs to bone [rich in the mineral hydroxyapatite (HA)], the calcium ion-chelating molecules of bisphosphonates represent a promising class of ligands (14). Bisphosphonates, upon systemic administration, are found to deposit in bone tissue, preferentially at the high bone turnover sites, such as the metastatic bone lesions, with minimal nonspecific accumulation (14) and were used herein to deliver NPs to the bone.A few systems explored for MM treatment have been tested in vitro including the following: (i) snake venom and silica NPs (15); (ii) thymoquinone and PLGA-based particles (16); (iii) curcumin and poly(oxyethylene) cholesteryl ether (PEG-Chol) NPs (17), polyethylenimine-based NPs for RNAi in MM (18), paclitaxel-Fe₃O₄ NPs (19), and liposomes (20). However, none of the above-mentioned systems have aimed to manipulate the bone marrow microenvironment rather than the myeloma cells directly (21). To date, there are no reports of using bone-targeted, controlled release, polymeric NPs with stealth properties for MM therapy. In this study, we designed NPs bearing three main components: (i) a targeting element that can selectively bind to bone mineral; (ii) a layer of stealth (PEG) to minimize immune recognition and enhance circulation; and (iii) a biodegradable polymeric material, forming an inner core, that can deliver therapeutics and/or diagnostics in a controlled manner. In this study, the physicochemical properties of a range of NPs was investigated (including NP size, charge, targeting ligand density, drug loading, and drug release kinetics) and an optimal formulation with ideal properties and maximal drug encapsulation was used for in vivo efficacy studies. We fine-tuned the NP targeting ligand density to optimize its bone-binding ability and further investigated its application for targeting myeloma in the bone microenvironment. We believe our NP system has the potential to increase drug availability by improving pharmacokinetics and biodistribution that can provide bone microenvironment specificity, which may increase the therapeutic window and most certainly decrease the off-target effects (12, 13).     

Morphological development of testes in ostrich (Struthio camelus) embryo

Although the histological structure of ostrich testis has been studied, very little information is currently available on the embryonic development of this organ. The aim of this study was to determine the sequence of the histological changes in diverse components of the testis in ostrich embryo from embryonic day (E) 20 to E42. The main findings were categorized into four histological features, i.e., development of sex cords, interstitial tissue and rete ducts, and the appearance of defective septa. While the lumen of sex cords, tunica albuginea, capsular rete ducts and Leydig cell precursors appeared at E26, the filum-shaped defective septa were visible at E36. The emersion of the lumen in the primary sex cords and formation of capsular rete ducts in the ostrich embryo is considerably different from that in other birds. However, tunica albuginea and Leydig cell precursors appeared in a similar pattern to those of other birds. An interesting observation was that the primordial germ cell (PGC)-like cells were completely distinct, while the capsular rete ducts were formed by trapping of some Sertoli cell aggregations in the tunica albuginea. This suggests that similar to the primary sex cords, the capsular rete ducts may originate from the Sertoli cell aggregations which had corralled some PGCs. Stereological estimations in the ostrich embryo testis showed the major proportion of testis is occupied by the seminiferous tubules, which is unlike the fowl embryo testis.     

Analgesic effects and hemodynamic mechanisms of perpendicular and transverse needling at Sanyinjiao (SP 6) in patients with primary dysmenorrhea: A randomized controlled trial

ObjectiveTo explore the analgesic effects and uterine hemodynamics of perpendicular needling (PN) and transverse needling (TN) at SP 6 in patients with primary dysmenorrhea (PD).MethodsIn this randomized controlled trial, patients with PD diagnosed with cold-dampness congealing pattern were randomly assigned in a ratio of 1:1 to receive PN or TN at bilateral SP 6 for 10 min. Acupuncture was performed when the menstrual pain score was over 40 mm on the first day of menstruation, as measured using the visual analog scale for pain (VAS-P). The primary outcome was average menstrual pain (VAS-P). Secondary outcomes included the pulsatility index (PI), resistance index (RI), and systolic-diastolic peaks ratio (S/D) in uterine arteries as measured using color Doppler ultrasonography; anxiety as assessed using the Hamilton Anxiety Rating Scale (HAMA), blood pressure (BP), and heart rate (HR).ResultsForty-eight patients completed the study. The TN group exhibited a significant reduction in VAS-P scores (–5.71 mm, 95% confidence interval (CI): –8.78, –2.63, P = .001), RI values (–0.05, 95% CI: –0.09, –0.01, P = .015), and HAMA values (–2.50, 95% CI: –4.78, –0.22, P = .032) when compared with the PN group. No significant differences in PI, S/D, BP, or HR values were observed between the two groups (P > .05).ConclusionTN at SP 6 was superior to PN in alleviating menstrual pain and anxiety in patients with PD. This analgesic effect of TN may be due to its better ability to improve uterine arterial blood flow via decreases in RI values.     

Anti-Cancer Effects of Traditional Medicinal Herbs on Oral Squamous Cell Carcinoma

Backgrounds: Oral squamous cell carcinoma (OSCC) is among the most frequent oral cancers in individuals under 40. Documents have endorsed that a diet enriched with fruit and vegetables can banish the risk of developing major cancers. This study aimed to evaluate the effects of different concentrations of four medicinal herbs including saffron, ginger, cinnamon and curcumin on OSCC cell line. Methods: Having obtained the aqueous extract of the four herbs, they were administered on OSCC cell lines per se and in dual, triple, and quadruple combinations. Their effects were measured in different concentrations and in 24 and 48 hours by using MTT assay. Results: The minimum and maximum effective concentrations were respectively 108 and 217 mg/ml for curcumin with IC30 of 77mg/ml, 108 and 270 mg/ml for ginger with IC30 of 58 mg/ml, 2 and 10 mg/ml for saffron with IC30 of 1.9 mg/ml, and 5 and 40 mg/ml for cinnamon with IC30 of 3.3 mg/ml. The best effect of the combinations was seen for cinnamon-saffron after both 24 and 48 hours and the four herbs combination after 48 hours. Conclusion: Although all the four herbs were effective on OSCC cell line, the strongest extract was saffron, followed by cinnamon. Combination of cinnamon-saffron and combination of the four herbs showed maximum effects. These findings suggest that traditional medicinal herbs may potentially contribute to oral cancer treatment; providing new windows for the development of new therapeutic strategies for OSCC.     

Utilisation des antagonistes de la GnRH au cours des stimulations pour inséminations intra-utérines : y a-t-il un intérêt ?

The use of the GnRH antagonists during ovarian stimulation for intrauterine insemination is relatively recent. The primary aim was to improve the timing of the inseminations on working days. However, according to published data, the consequences on pregnancy rate remain uncertain. Moreover, the impact of this strategy on stimulation's parameters, specifically on the size of the follicle cohort, should be better assessed.     

Epididymal leiomyosarcoma: Report of a rare case

Epididymal leiomyosarcoma (LMS) is a rare malignancy. Because the risk of recurrence is high, proper approach is important. Here, we present a patient with scrotal swelling who underwent surgical excision via scrotal incision, and the histopathological diagnosis was epididymal LMS. The decision was then made to perform inguinal radical orchiectomy.     

Longitudinal Tissue Velocity and Deformation Imaging in Inferobasal Left Ventricular Aneurysm

Background: Longitudinal myocardial tissue velocity imaging (TVI) and strain rate imaging (SRI) quantify regional myocardial function. We aimed to measure TVI and SRI indices for inferobasal aneurysmal segments by echocardiography at rest. Method: Sixteen patients with inferobasal left ventricular (LV) aneurysm, LV ejection fraction (EF) ≤50%, and 14 normal coronaries with normal echocardiography (control group) were studied. In SRI, peak systolic strain (ST), strain rate (SR), and pattern of strain curves and in TVI, peak systolic inward motion (Sm) were evaluated all at rest. Ascending curve means systolic expansion and descending means shortening. Results: LVEF was significantly lower in the patient group. Mean ST, SR, and Sm of inferobasal segment showed significant difference between patient and control groups; for ST: 1.45 ± 7.18% versus ?17.64 ± 7.45%, P < 0.0001; SR: ?0.25 ± 0.26 versus ?1.44 ± 0.64 sec^?1, P < 0.0001; and Sm: 3.85 ± 1.26 versus 5.56 ± 1.28 cm/sec, P = 0.006, respectively. All inferobasal aneurysmal segments had ascending curve while normal segments showed a descending curve. In patient group, aneurysmal segments had significantly reduced ST and SR compared to normal segments. Normal functioning segments of patients showed significant reduction of ST and SR compared to normal LV segments in control subjects. The range of SR and ST for inferobasal aneurysmal segments did not overlap with that of the normal segments (?0.60, 0.19 and ?3.00, ?0.80 sec^?1 for SR, and ?8.30, 23.30 and ?35.30, ?10.00% for ST, respectively). Conclusion: SRI indices were significantly reduced in inferobasal aneurysmal segment in comparison with either the same segment in normal subjects or normal functioning segments in the same patients. SR and ST may be superior to Sm in the evaluation of inferobasal aneurysmal segments. (Echocardiography 2010;27:803‐808)     

Anatomical retinal reattachment after scleral buckling with and without retinopexy: a pilot study

Purpose: To compare the anatomical results of scleral buckling with and without retinopexy and to assess the effect of retinopexy on the scleral buckling outcome. Methods: This randomized clinical trial was performed on 55 patients. Twenty‐two eyes were treated with scleral buckling (segmental or encircling) with or without drainage of subretinal fluid without any type of retinopexy (group 1); 33 patients received transscleral retinal cryopexy around retinal break(s) in addition to the former procedure. The two groups were matched regarding age, sex, myopia, aphakia, stage of proliferative vitroretinopathy (PVR) and number, type and location of the break(s). Results: In the non‐retinopexy group, 19 patients (86%) had complete retinal reattachment and one patient had partial reattachment after 34–48 months of follow‐up. One patient did not develop attachment because of missed break out of the buckle, and one had no attachment at all because of PVR. Overall success rate was 91% (20 of 22) in this group. In the retinal cryopexy group, 26 patients (79%) had complete retinal reattachment and two had partial reattachment during 35–56 months of follow‐up. In two patients, no attachment was achieved because of missed break out of the buckle; three patients developed redetachment after 1 and 3 months because of PVR. Overall success rate was 85% (28 of 33). The anatomical results in these two groups were the same statistically. Conclusion: With the permanent scleral buckling technique, retinal cryopexy adds no benefit to the success rate of anatomical retinal reattachment.     

Preliminary experiences with sentinel lymph node detection in cases of vulvar malignancy

Lymph node status is the most important prognostic factor in vulvar malignancy. The aim of this pilot study was to explore the clinical significance of radionuclide lymphoscintigraphy in the management of vulvar neoplasms. Eight patients with squamous cell carcinoma and two patients with malignant melanoma of the vulva were studied with 100 MBq technetium-99m nanocolloid (Sentiscint, OSSKI, Budapest) 1 day before surgery. The location of the sentinel lymph node was checked by a single-head gamma camera-computer system (MB 9200, Mediso, Budapest). Vulvectomy with bilateral inguinofemoral lymphadenectomy was performed in each case. At lymphadenectomy, the sentinel lymph node was separately removed and histologically studied. Three of the ten patients had positive sentinel lymph nodes (micrometastasis). Five months later one of them had local recurrence of the vulvar cancer, and another had inguinal recurrence of the tumour 6 months postoperatively; the third patient was operated on only recently. Our preliminary results are impressive and suggest that lymphoscintigraphy is an easy and reliable method for detection of the sentinel lymph node in vulvar malignancy.