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Non-muscle invasive bladder cancer is one of the most frequent forms of cancer. Commonly, the superficial tumor is removed by a minimal invasive surgery, mostly followed by the intravesical instillation of cytostatic agents. Although the initial treatment is usually successful, the recurrence rate is extraordinary high, which might be grounded in limiting factors during instillation, such as the high resistance of the bladder wall and the constant dilution with the permanently produced urine reducing the probability of interaction between the drug and the target cell. To overcome these limitations, we introduce a lectin-mediated drug delivery system consisting of wheat germ agglutinin as targeter, poly- l -glutamic acid as backbone and the active pharmaceutical ingredient (API) doxorubicin that should prolong the residence time in the bladder cavity. The optimized WGA-PGA-Doxo conjugate revealed an API load of 81 molecules per mole backbone and convinced in urothelial cell monolayer studies with an up to 56-fold higher cell-binding potential than pure doxorubicin. Additionally, the highly substituted drug delivery system not only internalized into urothelial cells, but also inhibited cell viability up to 99%. The combination of the high drug load with the promising cell-associative properties, which also revealed a higher affinity to malignant than to healthy urothelial cells, and the proven cytotoxic potential might lead to an improved efficacy of intravesical chemotherapy. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are among the most common bacterial infections. Despite a wide range of therapeutic options, treatment success is compromised by the efficient mechanism of tissue colonization of uropathogenic Escherichia coli. In advanced drug delivery systems, a similar, glycan-mediated targeting mechanism may be realized by conjugating the drug to a plant lectin, like wheat germ agglutinin (WGA). We introduce a drug delivery vehicle consisting of human serum albumin as nanoparticle shell, olive oil as core component, the active pharmaceutical ingredients (API) trimethoprim and rifampicin as well as WGA to facilitate cellular internalization. When WGA was embedded into the proteinaceous particle shell, cell binding studies revealed up to 60 % higher cell binding potential. Additionally, nanoparticles showed a good efficacy against gram-negative just as against gram-positive bacteria. The combination of the promising cell-associative properties and the proven antimicrobial potential might lead to an improved efficacy of advanced treatment of UTIs. The aim of this study was the development of a versatile drug delivery vehicle for an improved intravesical treatment of urinary tract infections. The development of antibiotic loaded WGA-functionalized nanoparticles might help to ensure enhanced bioavailability levels to improve treatment efficacy. Taken together, the data suggest that the here produced particles could serve as valid delivery vehicles providing the opportunity to follow and eradicate uropathogenic E. coli in their intracellular bacterial reservoirs resulting in an innovative and advanced treatment of urinary tract infections. [Display omitted] • Urinary tract infections are among the most common bacterial infections. • Uropathogenic Escherichia coli (UPEC) trigger uptake via a FimH lectin domain. • Uptake mechanism can be mimicked by protein nanoparticles (NPs) via plant lectins. • NPs have promising cell-associative properties and antimicrobial activity. • Versatile NPs might lead to an improved therapy of urinary tract infections. [ABSTRACT FROM AUTHOR]

The candidate pan-Human Papillomavirus (HPV) vaccine RG1-VLP are HPV16 major capsid protein L1 virus-like-particles (VLP) comprising a type-common epitope of HPV16 minor capsid protein L2 (RG1; aa17-36). Vaccinations have previously demonstrated efficacy against genital high-risk (hr), low-risk (lr) and cutaneous HPV. To compare RG1-VLP to licensed vaccines, rabbits (n = 3) were immunized thrice with 1 µg, 5 µg, 25 µg, or 125 µg of RG1-VLP or a 1/4 dose of Cervarix®. 5 µg of RG1-VLP or 16L1-VLP (Cervarix) induced comparable HPV16 capsid-reactive and neutralizing antibodies titers (62,500/12,500–62,500 or 1000/10,000). 25 µg RG1-VLP induced robust cross-neutralization titers (50–1000) against hrHPV18/31/33/45/52/58/26/70. To mimic reduced immunization schedules in adolescents, mice (n = 10) were immunized twice with RG1-VLP (5 µg) plus 18L1-VLP (5 µg). HPV16 neutralization (titers of 10,000) similar to Cervarix and Gardasil and cross-protection against hrHPV58 vaginal challenge was observed. RG1-VLP vaccination induces hrHPV16 neutralization comparable to similar doses of licensed vaccines, plus cross-neutralization to heterologous hrHPV even when combined with HPV18L1-VLP. [ABSTRACT FROM AUTHOR]

Cardiac Contractility Modulation devices (CCM) are novel devices that received FDA approval for use in patients with moderate to severe chronic heart failure (NYHA class III-IV), LVEF 25-45% and QRS <130ms with symptoms despite optimal medical therapy. CCM devices are pacemaker-like devices that function by delivering non-conducting electrical impulses to the right ventricular septum to augment intrinsic cardiac inotropy. While their use in this population has been established by prior research, few, if any, studies exist regarding CCM usage in patients with decompensated HF requiring inotropic support. An 80-year-old female presented to clinic with a history of hypertension, diabetes, chronic kidney disease, HFrEF (EF 25-30%, NYHA Class III) due to valvular disease, status-post transcatheter mitral valve replacement and ICD placement, requiring home milrinone for symptomatic control. She experienced worsening activity limitation requiring a wheelchair, decreased renal function, and reduced quality of life despite home intravenous inotropic support. She was referred to electrophysiology for consideration of CCM device implantation, which she received. Within 2 days after CCM placement (Impulse Dynamics, Marlton, NJ), milrinone was weaned off and GDMT was uptitrated. At follow up, she reported significant improvement in her exercise tolerance, no longer requiring a wheelchair, and being able to lie flat without symptoms. Additionally, she walked down 8 flights of stairs during a fire alarm without issue during a visit, demonstrating exercise capacity >4 METs. She has remained without repeat hospitalizations to date. CCM devices present a unique alternative for patients with decompensated heart failure requiring inotropic support. While additional research and long-term follow-up studies are needed to assess the efficacy of these devices, this case report represents the potential these devices have as a treatment modality for patients that have NYHA Class III or IV symptoms refractory to medical management. [ABSTRACT FROM AUTHOR]

• Short plasma half-life and high hydrophilicity of gemcitabine require high dosage. • Acylation of amino group provides tuneable lipophilicity and solubility. • Encapsulation in PLGA-nanoparticles enables API protection and controlled release. • Grafting the surface with wheat germ agglutinin imparts bioadhesive characteristics. After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary Objectives On the background of a high prevalence of HHV-8 infection in pre-pubertal Central African children, this study investigated the potential for in utero transmission of HHV-8. Patients Gabonese pregnant women were invited to provide peripheral and cord blood samples for serological and PCR diagnostics of HHV-8 infection at delivery for this cross-sectional survey. Results Out of 344 participants 120 (35%, 95% CI: 30-40%) were serologically positive for HHV-8. 31% (95% CI: 22-40%) of cord blood samples of seropositive women had detectable IgG antibodies. Among all seropositive participants HHV-8 was detected by PCR in one maternal peripheral blood sample at delivery (1%, 95% CI: 0.2-7%) and in none of cord blood samples. There was no association between demographic characteristics and infection status. Similarly, there was no difference in risk for premature delivery, low birth weight, and maternal anaemia in HHV-8 seropositive women. Discussion These data suggest a high seroprevalence of HHV-8 infection in pregnant women, however viraemia at delivery does not commonly occur in Central Africa. Based on these observations it may be speculated that infection of children may occur more commonly either antepartum or later on in infancy and childhood. [ABSTRACT FROM AUTHOR]