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Dermal papilla cells (DPCs) are one type of mesenchymal cells; they play a key role on hair follicle induction. Their hair inductivity and proliferation abilities are rapidly lost during the 2-dimensional culture. Cell senescence is induced by inadequate culture conditions and telomere shortening. We previously reported that overexpression of TERT coding telomerase reverse transcriptase and BMI1 coding human B-cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) avoided senescence of murine DPC and restored hair inductive activity.To evaluate the function of TERT and BMI1 in the human DPCs (hDPCs).Cultured hDPCs obtained from human scalp hair were transduced with TERT alone (hDP-T), BMI1 alone (hDP-B), both TERT and BMI1 (hDP-TB) and empty vector (hDP-E). The hair inductive activity of those cells was assessed by chamber assay in vivo. Gene expressions were analyzed by quantitative PCR (q-PCR).hDP-TB proliferated more than hDP-T and hDP-B in vitro and only hDP-TB showed hair inductivity in vivo. Moreover, the expressions of VCAN, CTNNB1, LEF1, FGF7 and VEGFA in hDP-TB were elevated compared to those in hDP-E.Overexpression of both TERT and BMI1 extends the life span of cultured hDPCs and ameliorates their hair inducing ability on mouse hair follicles.

8-Prenylnaringenin (8-PN), a hop flavonoid, is a promising food substance with health benefits. Compared with nonprenylated naringenin, 8-PN exhibits stronger estrogenic activity and prevents muscle atrophy. Moreover, 8-PN prevents hot flushes and bone loss. Considering that prenylation reportedly improves the bioavailability of flavonoids, we compared the parameters related to the bioavailability [pharmacokinetics and tissue distribution in C57/BL6 mice, binding affinity to human serum albumin (HSA), and cellular uptake in HEK293 cells] of 8-PN and its mother (non-prenylated) compound naringenin. C57/BL6 mice were fed an 8-PN or naringenin mixed diet for 22 days. The amount of 8-PN (nmol/g tissue) in the kidneys (16.8 ± 9.20), liver (14.8 ± 2.58), muscles (3.33 ± 0.60), lungs (2.07 ± 0.68), pancreas (1.80 ± 0.38), heart (1.71 ± 0.27), spleen (1.36 ± 0.29), and brain (0.31 ± 0.09) was higher than that of naringenin. A pharmacokinetic study in mice demonstrated that the Cmax of 8-PN (50 mg/kg body weight) was lower than that of naringenin; however, the plasma concentration of 8-PN 8 h after ingestion was higher than that of naringenin. The binding affinity of 8-PN to HSA and cellular uptake in HEK293 cells were higher than those of naringenin. 8-PN bioavailability features assessed in mouse or human model experiments were obviously different from those of naringenin.

O Serviço de Alimentação e Nutrição hospitalar é responsável não somente por produzir e distribuir refeições, é também sua função atender às necessidades do cliente hospitalizado. O objetivo deste estudo foi avaliar resultados de estratégias para melhoria da qualidade do Serviço de Alimentação e Nutrição de um hospital oncológico a partir da análise de fatores determinantes da qualidade na visão deste cliente. Após aplicação de questionário para conhecer graus de importância atribuídos às características da qualidade da alimentação, foram listados objetivos, resultados esperados e ações. Houve comparação da satisfação do cliente hospitalizado antes e após a implementação das estratégias. A frequência de respostas “satisfatório” relativas à aparência das refeições, atendimento da copeira e horário de refeições aumentou. Não houve aumento do percentual de aceitação da dieta, mas o motivo de não aceitação “características organolépticas” e “quantidade exagerada de alimentos”, dependentes do serviço de alimentação ofertado, apresentou redução da frequência. Dentre os motivos de não aceitação relacionados a doença, foi possível identificar prevalência sintomas consequentes ao tratamento quimioterápico, radioterápico ou cirúrgico a que o paciente oncológico é submetido como a falta de apetite e presença de distúrbios gastrointestinais nos dois momentos porém, com aumento de 73,73% para 79,29%, confirmando que a aceitação alimentar recebeu grande influência de fatores relacionados à doença.

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.

Background Pelvic floor muscles support the pelvic organs and control voiding. The first choice in the repair of pelvic floor function that is damaged during pregnancy and delivery is pelvic floor muscle training, which involves repeated muscle relaxation and contraction. However, as muscle contractions cannot be visualised, it is difficult to assess whether patients understand how to contract them. Therefore, we assessed patients’ comprehension of pelvic floor muscle contraction by comparing two teaching methods, vaginal palpation and transabdominal ultrasound, following vaginal delivery. We hypothesised that vaginal palpation is better than transabdominal ultrasound in this regard. Methods This randomised controlled trial conducted in facilities in Tokyo, Japan between July 2018 and January 2019 included women aged ≥ 20 years at 4–6 weeks after vaginal delivery. The randomisation involved website-based centralised allocation. The primary outcome was a change in bladder base displacement during pelvic floor muscle contraction before and after training, which was measured using transabdominal ultrasound. Participants performed three contractions for 3 s, and the mean value was used for statistical analysis. The secondary outcome was a change in understanding the contraction before and after training, which was measured using a five-point Likert scale questionnaire. Outcomes were analysed using Welch’s t-test. Results Sixty-five participants were randomly allocated to the vaginal palpation group (n = 32) and transabdominal ultrasound group (n = 33). Baseline characteristics were similar between the groups. Changes in bladder base displacement were not significantly different between the groups (p = 0.181). Within-group analyses showed that bladder base displacement was large in both groups after the respective intervention. There were no significant differences in any of the outcomes between the two groups before and after the intervention. Conclusions Vaginal palpation and transabdominal ultrasound might be useful for comprehending pelvic floor muscle contraction after vaginal delivery. Trial registration: UMIN 000032304. Registered 18 April 2018, https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000036820.

We conducted a stability study of biodegradable and amphiphilic nanoparticles (NPs) consisting of phenylalanine-attached poly(γ-glutamic acid) for drug delivery to find the optimal formulation and define the optimal storage conditions using novel quantitative analytical methods. The stability of NP suspension and lyophilized NP powder manufactured by a dimethyl sulfoxide-based and an ethanol-based process was assessed under 5°C, 25°C/60% relative humidity and 40°C/75% relative humidity. The content of phenylalanine-attached poly(γ-glutamic acid), impurities, absolute molecular weight, appearance, clarity of solution, particle size, zeta potential, particle matter, osmolality, water content, and pH were evaluated as parameters of NP stability. Lyophilized NPs with trehalose showed better stability. The lyophilized NP formulation could therefore provide a stable and high-quality product for clinical studies and shows promise as an effective drug delivery system carrier. The cardiotoxicity of prospective impurities contained in NPs and reagents used in the manufacturing process with human-induced pluripotent stem cell-derived 3-dimensional cardiomyocyte tissues by centrifugation layer-by-layer technique was also evaluated. As a result, cardiotoxicity for NPs and reagents was not observed, and it was clarified that the potential risk to human safety from NPs is low. The applicability of the cardiotoxicity evaluation approaches with human-induced pluripotent stem cell-derived 3-dimensional cardiomyocyte tissues will be evaluated by centrifugation layer-by-layer technique.

Many efforts have been made to achieve targeted delivery of anticancer drugs to enhance their efficacy and to reduce their adverse effects. These efforts include the development of nanomedicines as they can selectively penetrate through tumor blood vessels through the enhanced permeability and retention (EPR) effect. The EPR effect was first proposed by Maeda and co-workers in 1986, and since then various types of nanoparticles have been developed to take advantage of the phenomenon with regards to drug delivery. However, the EPR effect has been found to be highly variable and thus unreliable due to the complex tumor microenvironment. Various physical and pharmacological strategies have been explored to overcome this challenge. Here, we review key advances and emerging concepts of such EPR-enhancing strategies. Furthermore, we analyze 723 clinical trials of nanoparticles with EPR enhancers and discuss their clinical translation.

Parathyroid carcinoma is a rare condition, accounting for 1% of cases of hyperparathyroidism. Other causes of hyperparathyroidism main group are single adenoma and parathyroid hyperplasia. The clinics presented by the patients are typical of hyperparathyroidism (fatigue, weakness, weight loss, and anorexia), bone impairment, pain, and fractures, in addition to affecting the renal system The diagnosis of parathyroid carcinoma is most often done postoperatively by means of a histological study. The case report is a 49-year-old male patient who came to the emergency room of Mackenzie Evangelical University Hospital complaining of progressive “muscle weakness” and “joint” that started about 2 months ago. To raise the suspicion of parathyroid carcinoma, it is essential to perform the correlation of the clinical picture, biochemical values, and imaging exams, but to obtain the definitive diagnosis, intraoperative recognition of the tumor and the result of the histopathological examination of the resected tumor are necessary.

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O Projeto de Extensão “Gestão de Resíduos Sólidos Hospitalares” (PEGRSH) da Faculdades Pequeno Príncipe (FPP) teve início em 2014 visando minimizar o impacto do descarte inadequado de resíduos sólidos de saúde, buscando garantir a proteção dos trabalhadores, preservação da saúde pública e do meio ambiente.

A quantitative method of analyzing nanoparticles (NPs) for drug delivery is urgently required by researchers and industry. Therefore, we developed new quantitative analytical methods for biodegradable and amphiphilic NPs consisting of polymeric γ-PGA-Phe [phenylalanine attached to poly(γ-glutamic acid)] molecules. These γ-PGA-Phe NPs were completely dissociated into separate γ-PGA-Phe molecules by adding sodium dodecyl sulfate (SDS). The dissociated NPs were chromatographically separated to analyze parameters such as the γ-PGA-Phe content in the NPs, the impurities present [using reverse-phase (RP) HPLC with an ultraviolet (UV) detector], and the absolute MW [using size-exclusion chromatography (SEC) with refractive index detection (RI) and multiangle light scattering (MALS) detection, i.e., SEC-RI/MALS]. The chromatographic patterns of the NPs were equivalent to those of the component polymer (γ-PGA-Phe), and excellent chromatographic separation for the quantitative evaluation of NPs was achieved. To the best of our knowledge, this is the first report of the quantitative evaluation of NPs in the field of NP-based delivery systems. Furthermore, these methods were applied to optimize and evaluate the NP manufacturing process. The results showed that impurities were effectively removed from the γ-PGA-Phe during the manufacturing process, so the purity of the final γ-PGA-Phe NPs was enhanced. In addition, the appearance, clarity of solution, particle size, zeta potential, particle matter, osmolarity, and pH of the product were evaluated to ensure that the NPs were of the required quality. Our approach should prove useful for product and process characterization and quality control in the manufacture of NPs. γ-PGA-Phe NPs are known to be a powerful vaccine adjuvant, so they are expected to undergo clinical development into a practical drug-delivery system. The analytical methods established in this paper should facilitate the reliable and practical quality testing of NP products, thus aiding the clinical development of γ-PGA-Phe-based drug-delivery systems. Moreover, since these analytical methods employ commonly used reagents and chromatographic systems, the methods are expected to be applicable to other NP-based drug-delivery products too. Graphical abstract NPs were completely dissociated into separate γ-PGA-Phe polymeric molecules, which yielded a similar chromatogram to that seen for the NPs.

Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028. The apoptosis induction effect of low dose Poly-SNO-HSA on C26 cells in vitro under hypoxia can be restored by a phosphodiesterase 5 (PDE5) inhibitor, vardenafil. In C26-bearing mice, Poly-SNO-HSA/vardenafil combination treatment significantly suppressed the tumor volume compared with Poly-SNO-HSA or vardenafil treatment alone. Furthermore, the core tumor tissues showed increased expression of caspase-3 than the non-core tissue. The expression of caspase-3 appeared to overlap with the hypoxic zone of tumor tissues. Similar results were also obtained when the experiments were repeated using Epimedium extract, a natural herbal supplement with PDE5 inhibition activity. In conclusion, Poly-SNO-HSA/PDE5 inhibitors combination therapy is a promising approach for enhancing the anticancer therapeutic effects of Poly-SNO-HSA against not only anti-cancer drug resistance but also hypoxic stress related solid tumor resistance.

The number of deaths from air pollution worldwide is estimated at 8.8 million per year, more than the number of deaths from smoking. Air pollutants, such as PM2.5, are known to induce respiratory and cardiovascular diseases by inducing oxidative stress. Thioredoxin (Trx) is a 12-kDa endogenous protein that exerts antioxidant activity by promoting dithiol disulfide exchange reactions. We previously synthesized human serum albumin-fused thioredoxin (HSA-Trx), which has a longer half-life in plasma compared with Trx, and demonstrated its efficacy against various diseases including respiratory diseases. Here, we examined the effect of HSA-Trx on urban aerosol-induced lung injury in mice. Urban aerosols induced lung injury and inflammatory responses in ICR mice, but intravenous administration of HSA-Trx markedly inhibited these responses. We next analyzed reactive oxygen species (ROS) production in murine lungs using an in vivo imaging system. The results show that intratracheal administration of urban aerosols induced ROS production that was inhibited by intravenously administered HSA-Trx. Finally, we found that HSA-Trx inhibited the urban aerosol-induced increase in levels of neutrophilic extracellular trap (NET) indicators (i.e., double-stranded DNA, citrullinated histone H3, and neutrophil elastase) in bronchoalveolar lavage fluid (BALF). Together, these findings suggest that HSA-Trx prevents urban aerosol-induced acute lung injury by suppressing ROS production and neutrophilic inflammation. Thus, HSA-Trx may be a potential candidate drug for preventing the onset or exacerbation of lung injury caused by air pollutants., Graphical abstract Image 1, Highlights • HSA-Trx prevents urban aerosol-dependent lung injury. • HSA-Trx suppresses urban aerosol-induced reactive oxygen species (ROS) production. • HSA-Trx suppresses urban aerosol-induced neutrophilic extracellular traps (NETs) formation.

Zinc (Zn) plays an important role in many organisms in various physiological functions such as cell division, immune mechanisms and protein synthesis. However, excessive Zn release is induced in pathological situations and causes neuronal cell death. Previously, we reported that Cu ions (Cu2+) markedly exacerbates Zn2+-induced neuronal cell death by potentiating oxidative stress and the endoplasmic reticulum stress response. In contrast, the stress-activated protein kinase/c-Jun amino-terminal kinase (SAPK/JNK) signaling pathway is important in neuronal cell death. Thus, in this study, we focused on the SAPK/JNK signaling pathway and examined its involvement in Cu2+/Zn2+-induced neurotoxicity. Initially, we examined expression of factors involved in the SAPK/JNK signaling pathway. Accordingly, we found that phosphorylated (ie, active) forms of SAPK/JNK (p46 and p54) are increased by CuCl2 and ZnCl2 co-treatment in hypothalamic neuronal mouse cells (GT1-7 cells). Downstream factors of SAPK/JNK, phospho-c-Jun, and phospho-activating transcription factor 2 are also induced by CuCl2 and ZnCl2 co-treatment. Moreover, an inhibitor of the SAPK/JNK signaling pathway, SP600125, significantly suppressed neuronal cell death and activation of the SAPK/JNK signaling pathway induced by CuCl2 and ZnCl2 cotreatment. Finally, we examined involvement of oxidative stress in activation of the SAPK/JNK signaling pathway, and found that human serum albumin-thioredoxin fusion protein, an antioxidative protein, suppresses activation of the SAPK/JNK signaling pathway. On the basis of these results, our findings suggest that activation of ZnCl2-dependent SAPK/JNK signaling pathway is important in neuronal cell death, and CuCl2-induced oxidative stress triggers the activation of this pathway.

OBJECTIVE: To compare results of prebiotic, probiotic and synbiotic supplementation for the control of diarrhea in older patients receiving enteral nutritional therapy during hospitalization at a school hospital in Curitiba, state of Paraná. METHODS: The study was retrospective, by analysis of medical records corresponding to the visits performed between 2014 and 2018. RESULTS: A total of 75 patients were analyzed. The time of occurrence of diarrhea ranged from 1 to 16 days, with a mean of 2.69 days after the onset of therapy for reestablishment of the intestinal microbiota. As for the therapies introduced, 8 possible prescriptions of isolated and / or combined supplements were found as the first choice. Of the patients analyzed, 52% switched from supplementation during the occurrence of diarrhea; some using up to 5 different products. Of the 48% of patients who used a single product / combination from the beginning to the end of diarrhea, they generally started with a higher dose and decreased over time, with those starting at a lower dose having to increase it to stop diarrhea. In addition, there was statistical significance when comparing the time of diarrhea between patients who received a single product / combination and those who did supplemental exchanges throughout the treatment. CONCLUSION: Establishing a single prescription, whether of isolated or combined products and sticking to it, besides starting with a higher dose, seems more effective in controlling diarrhea in hospitalized geriatric patients, reinforcing the importance of establishing a protocol for prescription.

Resumo Este estudo objetiva refletir à luz da bioética a incorporação do conceito de direito à alimentação adequada no âmbito da terapia nutricional enteral. Trata-se de estudo longitudinal realizado com pacientes em nutrição enteral internados em hospital universitário brasileiro. O respeito a esse direito foi verificado a partir da análise de adequação da dieta oferecida aos pacientes. Os resultados demonstram que menos da metade dos pacientes recebeu dieta adequada (quantidade e qualidade), principalmente por fatores ligados a doenças e ao tratamento (diarreia, náuseas e vômitos, estase gástrica, jejum para exames/procedimentos). Entretanto, observa-se que limitação de recursos financeiros e fragilidades na organização dos serviços contribuem para essa realidade. A terapia nutricional enteral evoluiu nas últimas décadas em relação a regulamentações e disponibilidade de produtos, porém a análise bioética evidencia que há desafios a serem enfrentados para que o direito em questão seja garantido também no contexto clínico e terapêutico. Abstract This study aims to reflect, in the light of bioethics, about the incorporation of the concept of human right to adequate food in the scope of enteral nutritional therapy. This is a longitudinal study performed with patients being fed through enteral nutrition who were admitted to a Brazilian University hospital. The respect for this right was checked by the analysis of the adequacy of the diet offered to the patients. The results show that less than half the patients received adequate diet (quantity and quality), mainly due to disease and treatment factors (diarrhoea, nausea and vomiting, gastric stasis, fasting for exams/procedures). However, it is observed that the limitation of financial resources and fragility in the organisation of services contribute to this reality. Enteral nutritional therapy has evolved in recent decades in relation to regulations and availability of products, but bioethical analysis shows that there are challenges to be faced in order to ensure that the right in question is also guaranteed in the clinical and therapeutic context. Resumen Este estudio tiene como objetivo reflexionar, a la luz de la bioética, sobre la incorporación del concepto de derecho a la alimentación adecuada en el contexto de la terapia nutricional enteral. Se trata de un estudio longitudinal, realizado en pacientes con nutrición enteral internados en un hospital universitario brasileño. El respeto a este derecho se verificó a partir del análisis de la adecuación de la dieta ofrecida a los pacientes. Los resultados muestran que menos de la mitad de los pacientes recibieron una dieta adecuada (cantidad y calidad), principalmente debido a complicaciones relacionadas con la enfermedad y el tratamiento (diarrea, náuseas y vómitos, estasis gástrica, ayuno para exámenes/procedimientos). Sin embargo, se observa que la limitación de los recursos financieros y las debilidades en la organización de los servicios contribuyen a esta realidad. La terapia nutricional enteral ha evolucionado en las últimas décadas en relación con las regulaciones y la disponibilidad de productos, sin embargo, el análisis bioético muestra que hay desafíos a ser enfrentados para que el derecho en cuestión esté garantizado en el contexto clínico y terapéutico.

This integrative review was conducted to identify alternative tools for nutritional screening/evaluation of critically ill elderly patients that might overcome the limitations of traditional parameters. Four databases were searched. The criteria for inclusion were original articles, with full text available, published in Portuguese and English between 2013 and 2017. The search terms were: “elderly AND critical ill AND nutritional assessment” and “elderly AND intensive care AND nutritional assessment”. Nine articles were selected and divided between those using conventional and those using alternative nutritional parameters. At the end of I— the article selection stage, we found that none of the included studies used bioelectrical impedance analysis (BIA). Thus, an additional search was conducted, using the keywords “bioelectrical impedance analysis”, “bioelectrical impedance vector analysis”, “ “phase angle”, and “intensive care”, and articles related to the topic of interest were included. Studies using the Nutrition Risk in J2 Critical Ill (NUTRIC) score, which includes the Acute Physiology and Chronic Health Classification System II (APACHE II) and Sepsis-related Organ Failure Assessment (SOFA) scores, as well as those using either of these scores alone, presented good results. Although the final SOFA value remained the same in the studies included in this review, this instrument may be promising. We suggest that future research should explore the use of BIA (and its derived parameters, such as phase angle and bioelectrical impedance vector analysis - BIVA) and combinations of the NUTRIC score with phase angle and/or BIVA in critically ill elderly patients with decreased level of consciousness and/or edema.

The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors, and it can serve as a basis for the development of macromolecular anticancer therapy. We have previously found that recombinant human serum albumin dimer, and especially its S-nitrosated form (SNO-HSA-Dimer), is an enhancer of the EPR effect. In this study, we investigated the influence of SNO-HSA-Dimer on the anti-tumor effect of two types of macromolecular anti-tumor drugs, namely N-(2-hydroxypropyl)methacrylamide polymer conjugated with zinc protoporphyrin, which forms micelles and can be used for fluorescence studies. The other was PEGylated liposomal doxorubicin (Doxil), a typical example of a stealth liposome approved for medical usage. In mice having C26 tumors with highly permeable vasculature, SNO-HSA-Dimer increases tumor accumulation of the drugs by a factor 3-4 and thereby their anti-tumor effects. Experiments with Evans blue revealed increased EPR effect in all parts of the tumor. Furthermore, SNO-HSA-Dimer improves the anti-metastatic effects of Doxil and reduces its minor uptake in non-tumorous organs such as liver and kidney. Tumor accumulation of Doxil in B16 tumors, which are characterized by a low permeable vasculature, increased even more (6-fold) in the presence of SNO-HSA-Dimer, and the improved accumulation lead to decreased tumor volume and increased survival of the animals. The administration of SNO-HSA-Dimer itself is safe, because it has no effect on blood pressure, heart rate or on several biochemical parameters. The present findings indicate that SNO-HSA-Dimer is promising for enhancing the EPR effect and consequently the specific, therapeutic effects of macromolecular anticancer drugs.

Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short-term therapeutic effects, whereas long-term therapeutic benefits are rarely observed, probably due to hypoxia-induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S-nitrosated human serum albumin (SNO-HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO-HSA significantly suppressed hypoxia-induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO-HSA was also confirmed in vivo by combining it with Bev. In C26-bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO-HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO-HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO-HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO-HSA to suppress autophagy-mediated drug resistance and enhance the efficacy of chemotherapy.

Amphiphilic graft copolymer consisting of poly(γ-glutamic acid) (γ-PGA) as the hydrophilic backbone and L-phenylalanine ethyl ester (Phe) as the hydrophobic side chain is an important biodegradable polymer with great potential in medical applications. In this research, we established analytical methods for the characterization and quality control of γ-PGA-graft-Phe (γ-PGA-Phe), which forms nanoparticles in aqueous solution, as a deployment platform in practical applications for vaccine adjuvants. The SEC-RI/MALS system, which uses size exclusion chromatography (SEC) coupled with a multi_angle light scattering (MALS) detector and refractive index (RI) detector, was developed to evaluate the characteristics of various types of polymers. By this method, it was indicated that absolute molecular weight (MW) should be used to measure the branch polymer. A gradient reversed phase HPLC (RP-HPLC) method was developed for the content of γ-PGA-Phe and the impurity levels to control product quality and safety. This quantitative approach could become key elements for identifying and characterizing γ-PGA-Phe. In addition, the degradation mechanism of γ-PGA-Phe was also identified as cleavage of main-chain of γ-PGA-Phe based on the stability study of γ-PGA-Phe in buffer solution with various pH values. The analytical developments described above will be important for use in both characterization and formulation design of biopolymers. Nanoparticles (NPs) composed of well-characterized biodegradable γ-PGA-Phe are expected to have a variety of potential clinical applications such as their use as drug and vaccine carriers.

After mechanical cleaning in oral care, eliminating residual oral contaminants has an important role in preventing their aspiration, especially in individuals with weak airway protection. We examined the effectiveness of wiping the oral cavity after oral care on eliminating contaminants in 31 patients who were hospitalized in our neurology inpatient unit. The amount of bacteria on the tongue, palate, and buccal vestibule was counted before and just after oral care, after eliminating contaminants either by rinsing with water and suction or by wiping with mouth wipes, and 1 h after oral care. Oral bacteria amounts were decreased significantly by both elimination procedures after oral care. These findings suggest that wiping with mouth wipes is as effective as mouth rinsing to decrease bacteria following oral care. With a lower risk of contaminant aspiration, wiping may be a suitable alternative to rinsing, especially in dysphagic individuals.

Background Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive form of MEN2. MEN2B cases usually carry either an M918T or A883T mutation of the RET, but to date, there are 3 atypical MEN2B caused by tandem mutations. Methods and Results A 32-year-old woman with no family history of medullary thyroid carcinoma (MTC) presented with a neck tumor and multiple mucosal nodules. She was diagnosed with MEN2B. Genetic analyses of RET revealed that she had 2 mutations, Q781R and V804M. Subclone and genetic analyses revealed that Q781R was on the paternal allele and V804M was a de novo. In silico analysis of the tandem mutations showed a high prediction score. Conclusions We describe a novel combination of tandem RET mutations (Q781R/V804M) in a MEN2B-like patient. In silico analysis showed a high prediction score, which was compatible with the clinical phenotype in the present case. © 2012 Wiley Periodicals, Inc. Head Neck 35: E363–E368, 2013

Hydrogen sulfide (H2S) signaling involves polysulfide (RSSnSR') formation on various proteins. However, the current lack of sensitive polysulfide detection assays poses methodological challenges for understanding sulfane sulfur homeostasis and signaling. We developed a novel combined assay by modifying Sulfide Antioxidant Buffer (SAOB) to produce an "Elimination Method of Sulfide from Polysulfide" (EMSP) treatment solution that liberates sulfide, followed with methylene blue (MB) sulfide detection assay. The combined EMSP-MB sulfide detection assay performed on low molecular weight sulfur species showed that sulfide was produced from trisulfide compounds such as glutathione trisulfide and diallyl trisulfide, but not from the thiol compounds such as cysteine, cystine and glutathione. In the case of plasma proteins, this novel combined detection assay revealed that approximately 14.7, 1.7, 3.9, 3.7 sulfide mol/mol released from human serum albumin, α1-anti-trypsin, α1-acid glycoprotein and ovalbumin, respectively, suggesting that serum albumin is a major pool of polysulfide in human blood circulation. Taken together with the results of albumins of different species, the liberated sulfide has a good correlation with cysteine instead of methionine, indicating the site of incorporation of polysulfide is cysteine. With this novel sulfide detention assay, approximately 8,000, 120 and 1100 μM of polysulfide concentrations was quantitated in human healthy plasma, saliva and tear, respectively. Our promising polysulfide specific detection assay can be a very important tool because quantitative determination of polysulfide sheds light on the functional consequence of protein-bound cysteine polysulfide and expands the research area of reactive oxygen to reactive polysulfide species.

This study aimed to determine the characteristics of the quality required for patients regarding alimentation during hospitalinternment. Patients interned in apartments and infirmaries of two general hospitals of Curitiba City-PR, answered a questionnaire thatevaluated the relevance of nine characteristics of quality. Results showed that the characteristics of temperature, flavor, hygiene, menu,courtesy of feeding service and adequate utensils for meals were considered very important by hospitalized customers. The knowledgeof hospital alimentation quality determinants must be the starting point for the development of strategies to care for necessities ofcustomers, preventing that factors related to the service offered by the Unit of Feeding and Nutrition negatively influence the acceptanceof foods by hospitalized patients.

Aim: The aim of this study was to develop an age estimation table based on mineralization stages of third molars in a survey in the state of Alagoas, Brazil. Forensic dentistry has largely contributed to solve age estimation cases. Radiographic study on tooth mineralization stages has shown major importance on age estimation with forensic application. Methods: This investigation was a crosssectional study developed at the clinic of the local branch of the Brazilian Dental Association in Alagoas. Three hundred and twelve patients of both genders aged 9 to 21 years were enrolled. Three calibrated examiners (kappa=0.789, p

Com o objetivo de verificar os resultados de um protocolo diferenciado, no que se refere a especificidades no trabalho de pré-operatório e à evolução para dieta sólida a partir da 3ª semana de pós-operatório, foram estudados 100% dos pacientes atendidos durante o período de abril de 2000 a agosto de 2001. Um total de 50 pacientes que apresentavam variação do Índice de Massa Corporal de 40kg/m² a 55kg/m² foram avaliados. Os resultados obtidos, tanto no pré quanto no pós-operatório, foram positivos, mostrando que 60% dos pacientes no pré-operatório reduziram seu peso. No pós-operatório, até o 21º dia de alimentação, os resultados foram favoráveis quanto à perda de peso e mostraram baixa incidência das principais complicações deste período, relatadas em literatura. Assim, enfatiza-se a importância da elaboração de um protocolo de atendimento nutricional que contemple e priorize aspectos de educação nutricional, preparo cuidadoso do paciente no pré-operatório e monitorização detalhada no pós-operatório.The goal of this research is to verify the results of a differentiated protocol that refers to the particularities in the preoperative period and the evolution of the solid diet after the 3rd week of the postoperative period. Between April 2000 and August 2001, 100% of the attended patients were studied. A total of 50 patients, with BMI variation between 40kg/m² and 55kg/m² were observed. The obtained results in pre and postoperative periods were positive, and demonstrated that 60% of the patients reduced their weight. Until the 21st day with oral feeding in postoperative period, patients demonstrated satisfactory results in terms of weight loss and low incidence of the main complications related to this period, as described in literature. Therefore, it is important to elaborate a Nutritional Attendance Protocol that contemplates and prioritizes nutritional education aspects, the preparation of the patient before surgery and detailed monitoring after surgery.

The heat capacity of the cubic mesogen ACBC(16) was measured between 16 and 500 K by adiabatic calorimetry. As well as the known condensed phases, a new crystalline phase was found to undergo a glass transition at around 165 K. Phase transitions between crystal, SmC, cubic, and isotropic liquid phases took place at 399.16, 431.15, and 474.30 K, respectively. As in the case of ANBC, a broad hump was observed in the heat capacity of the isotropic liquid phase. The first order nature of the SmC–cubic phase transition was confirmed for the first time by the observation of supercooling of the cubic phase. The broad hump in the isotropic liquid phase was shown to extend to a low temperature side if the isotropic liquid was supercooled, suggesting that the event occurring at the hump is not directly related to the cubic–isotropic liquid phase transition.

Meaning of the alkyl chain-length dependence of transition entropy in liquid crystal is discussed and clarified in a long-chain region. A method to deduce contributions of the alkyl chain and the molecular core is proposed. Application of the method suggests that, in most smectic A (SmA) - nematic (N) phase transitions, not only a molecular core (modeled by a hard-rod) but also a (terminal) alkyl chain is disordered upon the SmA→N transition.