Finding the best therapeutic approach for PCOS: the importance of inositol(s) bioavailability.

Broadening clinical evidence has markedly designated inositol(s) as a common and effective therapeutic approach for PCOS and infertility. Although considerable research has been focused on the use in clinical practice of myo-inositol (myo-ins) and D-chiro-inositol (D-chiro-ins), the two major inositol stereoisomers, less attention has been paid to their bioavailability. Therefore, the aim of this paper is to gather and analyze information on inositol(s) bioavailability, to better delineate its optimal concentration for scientific and clinical purposes. Throughout the search in PubMed, Google Scholar, and ResearchGate we identified only two studies that investigated the pharmacokinetic (PK) profile of different myo-ins administrations. This analysis found no advantage in terms of PK for single 4 g dosing of myo-ins compared to 2 g twice a day, which allowed to get a 24-hour coverage, contrary to the singular dose. Indeed, the differences regarding the area under the curve (AUC) between the two PK profiles are linked only to the maximum concentration (Cmax) but not to the time variable. In conclusion, splitting the therapeutic dosage of 4 g myo-ins in two distinct administrations seems to be the best approach for a full-day coverage.

hMENA(11a) contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA(11a) and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA(11a) isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA(11a) is involved in these resistance mechanisms. The specific hMENA(11a) depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA(11a) phosphorylation and affected its localization. At the functional level, we found that hMENA(11a) sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA(11a) silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA(11a) contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA(11a) in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA(11a) expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA(11a) activity could represent a new target for antiproliferative therapies in breast cancer.

Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak.

OBJECTIVE: To compare the efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine with the commercially available influenza hemagglutinin-subunit vaccine in preventing influenza in older adults living in a nursing home. DESIGN: A prospective, randomized, double-blind vaccine trial with 5 months of follow-up after vaccination. SETTING: Fourteen Wisconsin nursing homes. PARTICIPANTS: Nursing home residents at least 65 years old who were able to give informed consent and were free of malignancy and not receiving immunosuppressive therapy. INTERVENTIONS: Participants received, by intramuscular injection, 0.5 mL of a trivalent influenza vaccine containing 15 micrograms each of A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), and B/Ann Arbor/1/86 (HA) or 0.5 mL of an influenza vaccine containing the same antigens conjugated to diphtheria toxoid (HA-D). MEASUREMENTS: Blood was obtained pre- and 1 month post-vaccination to assess for any vaccine-induced antibody titer change. Clinical surveillance for respiratory illness was performed twice weekly for 5 months. A record was kept of all signs and symptoms of new respiratory illness, and a viral culture and acute and convalescent sera were obtained. RESULTS: 204 participants received HA and 204 received HA-D. Both groups had similar baseline antibody levels to all influenza antigens. HA-D recipients seroconverted more frequently based on serum neutralizing activity (P < 0.05), had a greater increase in geometric mean titer (GMT), and sustained the increase in antibody titer longer than HA recipients. Vaccine hemagglutinin recall was greater in a subset of HA-D recipients as measured by lymphocyte proliferative assays (P < 0.05). During an outbreak of influenza A (H3N2 A/Shanghai/11/87-like and A/Victoria/7/87-like), fewer HA-D (29/195) than HA (43/204) recipients had laboratory-confirmed infection (P = 0.053), and, of these, fewer HA-D-treated subjects had lower respiratory tract involvement (5/29 HA-D and 17/43 HA) (P = 0.022). CONCLUSIONS: HA-D was more immunogenic in institutionalized elderly recipients and produced greater protection from influenza infection. Superior protection may be due to HA-D's ability to stimulate and recruit antigen-presenting cells, thus enabling the recipient to achieve and maintain functional antibody titers.

Measles severity and serum retinol (vitamin A) concentration among children in the United States.

BACKGROUND: Studies in developing countries have shown that children with measles have low serum retinol concentrations and that lower retinol levels are associated with measles-related mortality. Vitamin A therapy has been shown to reduce mortality among African children with acute measles. OBJECTIVES: To determine whether serum retinol concentration is low among children with measles in the United States and to determine whether retinol concentration is associated with illness severity. SETTING: Pediatric referral hospital and clinic in Milwaukee, WI, during the measles outbreak of 1989-1990. PATIENTS: One hundred fourteen patients < or = 5 years of age evaluated for serologically confirmed measles with serum obtained within 5 days following rash onset. METHODS: Serum retinol concentration was determined by high-performance liquid chromatography. Clinical data were collected by hospital record review. A modified Pediatric Risk of Mortality (PRISM) score was used to assess physiologic instability as a measure of illness severity. RESULTS: Retinol concentrations ranged from 0.25 to 1.18 mumol/L (median 0.58 mumol/L); 82 (72%) patients had low retinol concentration (< or = 0.70 mumol/L). Median retinol concentrations were lower among hospitalized patients (0.56 vs 0.70, P = .006) and patients with pneumonia (0.52 vs 0.64, P = .02) but higher among children with otitis media (0.63 vs 0.54, P = .01). Higher modified PRISM scores, reflecting greater physiologic instability, were associated with lower retinol concentration (beta coefficient -.0147, P = .025). In multivariate analysis, higher modified PRISM scores were associated with lower retinol concentration (beta coefficient -.0144, P = .025) even after controlling for hospitalization, presence of complications, race, age, receipt of Aid to Families With Dependent Children, gender, and interval from rash onset until serum was collected. CONCLUSIONS: Among these children with measles in an urban United States community, retinol concentrations were depressed, and the degree of depression was associated with illness severity. Vitamin A therapy should be considered for children with measles in the United States who require hospitalization.

Emergence and possible transmission of amantadine-resistant viruses during nursing home outbreaks of influenza A (H3N2).

Outbreaks of influenza A (H3N2, A/Shanghai/11/87-like) occurred in two partially (60% and 79%) vaccinated nursing home populations in January 1988. A retrospective cohort study using chart review was designed to assess the effectiveness of influenza vaccination and amantadine prophylaxis (100 mg per day) in controlling the outbreaks and to determine the amantadine susceptibility of influenza viruses isolated from case-patients. The point estimate of vaccine efficacy in preventing influenza-like illness was -33% (95% confidence interval -115% to 18%). However, 9% of vaccinated case-patients died within 14 days after onset of influenza-like illness compared with 26% of unvaccinated case-patients (relative risk = 0.4, 95% confidence interval 0.1-1.0). There was no significant difference in illness severity among case-patients who became ill before amantadine prophylaxis was started (n = 84) compared with those who became ill while taking amantadine (n = 34). Four virus isolates obtained before amantadine prophylaxis was started demonstrated 52-68% inhibition by 1 microgram/ml of amantadine; by comparison, six isolates (resistant viruses) obtained from residents who became ill while taking amantadine demonstrated 1-18% inhibition. The resistant viruses had four different RNA sequences in the gene coding for the M2 protein transmembrane region. Three resistant viruses with identical RNA sequences were isolated from residents living in contiguous rooms who had onset of signs and symptoms during a 6-day interval. Further studies are needed to determine how frequently and under what circumstances resistant viruses occur when antiviral agents are used to control institutional influenza A outbreaks. Strategies for antiviral agent administration that limit the emergence and transmission of resistant virus strains may be needed.