2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents.

PURPOSE: This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer. METHODS: A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses. RESULTS: Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented. CONCLUSION: There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

An endoscopic hydro-mastoidectomy technique for cholesteatoma surgery.

OBJECTIVE: Endoscopic hydro-mastoidectomy, in which mastoidectomy is performed underwater, can be employed during transcanal endoscopic ear surgery for cholesteatoma removal. It was hypothesised that endoscopic hydro-mastoidectomy might take less time than endoscopic non-underwater mastoidectomy because the endoscope does not need to be removed for cleaning. METHODS: This study compared the mastoidectomy and total operative durations between the endoscopic hydro-mastoidectomy (n = 25) and endoscopic non-underwater drilling (control, n = 8) groups. Moreover, it compared the size of resected areas of the external auditory canal between the two groups. RESULTS: The mastoidectomy time of the endoscopic hydro-mastoidectomy group was significantly shorter than that of the control group (p < 0.01). The total operative time did not differ significantly between the endoscopic hydro-mastoidectomy and control groups (p = 0.17). The resected area was significantly larger in the endoscopic hydro-mastoidectomy group than in the control group (p < 0.05). CONCLUSION: Endoscopic hydro-mastoidectomy enables more extensive bone resection within a shorter period.

A maintained absolute lymphocyte count predicts the overall survival benefit from eribulin therapy, including eribulin re-administration, in HER2-negative advanced breast cancer patients: a single-institutional experience.

PURPOSE: Eribulin methylate (eribulin) improved the overall survival (OS) of HER2-negative advanced breast cancer (HER2-ABC) patients; however, the mechanism underlying the OS improvement has not been clarified. Several reports suggest that eribulin promotes antitumor immunity via tumor micro-environment conditioning. Recently, a maintained baseline lymphocyte count was proposed as predictive marker for eribulin therapy in HER2-ABC patients; however, no associations with the OS have been noted. We retrospectively investigated the neutrophil-to-lymphocyte ratio and absolute lymphocyte count (ALC) in HER2-ABC patients receiving eribulin and assessed the utility of eribulin re-administration for further OS improvement. METHODS: HER2-ABC patients who received eribulin therapy at Shizuoka Cancer Center between November 2011 and December 2018 were retrospectively analyzed. RESULTS: A total of 144 HER2-ABC (108 estrogen receptor-positive [ER+], 36 ER-) patients were identified, and 32 patients (28 ER+ , 4 ER-) were re-administered with eribulin. In the ER+ subgroup, a multivariate analysis showed that an ALC ≥ 1000/µL and re-administration were significantly associated with the OS (hazard ratio [HR] 0.503; P = 0.034 and HR 0.366; P < 0.0001, respectively), and an ALC ≥ 1000/µL was also identified as the only predictive factor for re-administration (HR 0.329; P = 0.033). In contrast, a multivariate analysis in the ER- subgroup identified no predictive markers. CONCLUSION: In HER2-ER + ABC patients, ALC was identified as a predictive marker for eribulin therapy, and the re-administration of eribulin is considered a valid therapeutic option for further improvement of the OS.

Clinical biochemistry of rescued Magellanic Penguins (Spheniscus magellanicus): serum or heparinized plasma? / Bioquímica clínica de pinguins-de-magalhães (Spheniscus magellanicus) de resgate: soro ou plasma heparinizado?

IIn the last few years, an increasing number of debilitated Magellanic penguins (Spheniscus magellanicus) has been rescued and taken to rehabilitation centers on Brazil's southern coast to be clinically treated and evaluated for re-introduction. This work aims to compare the viability of heparinized plasma with the viability of serum for biochemistry analyses under rehabilitation conditions. Blood sampled from 31 physically healthy rescued penguins was processed into serum/plasma-paired samples and analyzed for 12 biochemical parameters: alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), cholesterol (CHOL), creatine kinase (CK), gamma-glutamyl transpeptidase (GGT), glucose, (GLU) lactate dehydrogenase (LDH), total proteins (TP), triglycerides (TG), urea (UR), and uric acid (UA).The results showed that six paired samples presented visual signs of hemolysis (visual hemolytic score≥1), four of which occurred exclusively in the serum counterpart. Significant differences (P≤ 0.5) between sample types were found for CHOL (3%), GLU (6%) and TG (52%). Only TG was considered clinically relevant (>10%). All mean/median results fell within the available reference intervals by the Association of Zoos and Aquariums (Penguin, 2014). In conclusion, we verified that heparinized plasma is a viable sample for the clinical biochemistry of rescued Magellanic penguins as it yields compatible results with serum, while providing practical benefits. The adoption of this practice favors a faster bird recovery, by minimizing blood sampling volume, and optimizes material resources, allowing use of the same collector tube as for hematology.(AU)

Nos últimos anos, um número crescente de pinguins-de-magalhães (Spheniscus magellanicus) debilitados vem sendo resgatado e encaminhado aos centros de reabilitação do litoral sul do Brasil para cuidados clínicos e posterior avaliação de reintrodução. Este trabalho teve como objetivo comparar a viabilidade do plasma heparinizado com a do soro para análises bioquímicas, em condições de reabilitação. Amostras de sangue de 31 pinguins de resgate fisicamente saudáveis foram processadas em amostras pareadas de soro e plasma heparinizado, e 12 parâmetros bioquímicos foram analisados: alanina aminotransferase (ALT), fosfatase alcalina (ALP), aspartato aminotransferase (AST), colesterol (CHOL), creatina quinase (CK), gamaglutamil transpeptidase (GGT), glicose (GLU), lactato desidrogenase (LDH), proteínas totais (TP), triglicérides (TG), ureia (UR) e ácido úrico (UA). Os resultados mostraram que seis amostras pareadas apresentaram sinais visuais de hemólise (escore hemolítico visual≥1), das quais quatro ocorreram exclusivamente no soro. Observaram-se diferenças significativas (P≤0,5) entre os tipos de amostra em CHOL (3%), GLU (6%) e TG (52%), sendo apenas TG considerado clinicamente relevante (>10%). Todos os resultados de médias e medianas situaram-se dentro dos intervalos de referência disponíveis fornecidos pela Associação de Zoológicos e Aquários (AZA). Como conclusão, verificou-se que o plasma heparinizado é uma amostra viável para a bioquímica clínica de pinguins-de-magalhães de resgate, produzindo resultados compatíveis com os do soro. Além disso, a adoção dessa prática favorece uma recuperação mais rápida dos animais, ao diminuir o volume de sangue amostrado, e otimiza os recursos materiais, ao permitir o aproveitamento do mesmo tubo de colheita de hematologia.(AU)

Anti-ß2 -glycoprotein I antibody with DNA binding activity enters living monocytes via cell surface DNA and induces tissue factor expression.

Autoantibodies characteristic for anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are anti-ß2 -glycoprotein I (ß2 GPI) antibodies and anti-DNA antibodies, respectively, and almost half of APS cases occur in SLE. Anti-ß2 GPI antibodies are recognized to play a pivotal role in inducing a prothrombotic state, but the precise mechanism has not been fully elucidated. In a widely accepted view, binding of anti-ß2 GPI antibodies to cell surface ß2 GPI in monocytes and endothelial cells triggers the Toll-like receptor 4-myeloid differentiation primary response 88 (TLR)-4-MyD88) signaling pathway which leads to activation of p38 mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinases (MEK-1/ERK) and/or nuclear factor kappa B (NF-κB) and expression of tissue factor (TF). However, resting cells do not express substantial amounts of TLR-4. Previously, we generated a mouse monoclonal anti-ß2 GPI antibody WB-6 and showed that it induced a prothrombotic state - including TF expression on circulating monocytes - in normal mice. In the current study, we aimed to clarify the mechanism of interaction between WB-6 and resting monocytes, and found that WB-6 exhibits binding activity to DNA and enters living monocytes or a monocytic cell line and, to a lesser extent, vascular endothelial cells. Treatment of the cells with DNase I reduced the internalization, suggesting the involvement of cell surface DNA in this phenomenon. Monocytes harboring internalized WB-6 expressed TF and tumor necrosis factor (TNF)-α which, in turn, stimulated endothelial cells to express intercellular adhesion molecule 1 (ICAM-I) and vascular cell adhesion molecule 1 (VCAM-I). These results suggest the possibility that a subset of anti-ß2 GPI antibodies with dual reactivity to DNA possesses ability to stimulate DNA sensors in the cytoplasm, in addition to the cell surface receptor-mediated pathways, leading to produce proinflammatory and prothrombotic states.

Sézary syndrome managed with histone deacetylase inhibitor followed by anti-CCR4 monoclonal antibody.

A 70-year-old man presented to our clinic with a 10-year history of recurrent pruritic erythema and plaques on his trunk and limbs. Based on the pathological findings and monoclonal rearrangement of the T-cell receptor (TCR)-Cß1 gene, mycosis fungoides (T2N0M0B0 stage IB) was diagnosed. Despite combination therapy including histone deacetylase inhibitor (vorinostat), the symptoms slowly evolved into Sézary syndrome (SS; T4N1M0B2) over 4 years, with dense infiltrates due to atypical lymphocytes expressing CCR4 developing in the entire dermis. Anti-CCR4 monoclonal antibody (mogamulizumab) treatment was started. After seven courses, the CCR4-positive atypical lymphocytes decreased in the dermis to levels below those seen at the outset of treatment. To our knowledge, there is no previous report of a case of SS managed with vorinostat followed by mogamulizumab demonstrating such a remarkable change in the pathological state following treatment.

Efeito de diferentes intensidades de exercício em esteira sobre os parâmetros eletrocardiográficos de cães hígidos / Effect of different intensities of treadmill exercise on eletrocardiographic parameters of healthy dogs

Objetivou-se a padronização de testes de exercício de alta e baixa intensidades em esteira, bem como a avaliação do eletrocardiograma de cães submetidos a esses testes. Para tal fim, sete cães da raça Australian Cattle Dog e quatro da raça Border Collie clinicamente saudáveis foram submetidos a dois testes de exercício em esteira, com pelo menos sete dias de intervalo: T1 - teste de exercício de alta intensidade e curta duração, e T2 - teste de exercício de baixa intensidade e longa duração. A amplitude e a duração de ondas e intervalos foram avaliadas no momento antes do exercício (M0) e nos momentos imediatamente após o término dos testes (MPE) e 30 minutos após (M30). A frequência e o ritmo cardíacos foram avaliados antes dos testes e continuamente por 30 minutos após o término do exercício. Verificou-se diferença significativa somente para a duração do intervalo QT em M30 em T1, além de algumas arritmias, como complexos atriais e ventriculares prematuros isolados em três animais após o teste T1, e em quatro após T2. Os testes de exercício foram adequados para promover estimulação simpática nos cães, contudo não causaram alterações significativas no eletrocardiograma, provavelmente em razão do excelente condicionamento físico dos animais.(AU)

This study aimed to stardardize high and low intensity exercise tests, and evaluate the electrocardiogram of dogs submitted to these tests. Seven clinically healthy Australian Cattle dogs and four Border Collies underwent two exercise treadmill tests, with at least a seven day interval: T1 - high intensity and short duration exercise test, and T2 - low intensity and long duration exercise test. Amplitude and duration of waves and intervals were assessed at resting time before exercise (M0), at immediately after (MPE) and at 30 minutes (M30) after the end of the tests. Heart rate and cardiac rhythm were evaluated before the tests and continuously for 30 minutes after the end of exercise. There was a significant difference only for duration of the QT interval at M30 in T1, and some arrhythmias such as isolated atrial and ventricular premature complexes in three animals after T1 test, and in four dogs after T2. The exercise tests of the present study was suitable to promote sympathetic stimulation in dogs, however did not cause significant changes on the electrocardiogram probably because of the excellent physical fitness of the dogs.(AU)

Características eletrocardiográficas de éguas da raça Crioula em diferentes fases do período gestacional / Electrocardiographic features of Crioulo mares in different pregnancy stages

Pregnancy can cause several physiologic changes in mares, including modifications in cardiac output and heart positioning. Therefore, these changes could influence electrocardiographic parameters in various stages of pregnancy. This study aimed to evaluate the electrocardiogram of Crioulo mares in different pregnancy stages. Nine non pregnant mares (G0), 11 mares at three months (G3), 11 mares at six months (G6) and 11 mares at 10 months of pregnancy (G10) were submitted to electrocardiographic evaluation. There was higher (P= 0,002) heart rate of G10 (60.45±12.16bpm) when compared to other groups (G0=45.67±10.75bpm; G3=44.91±7.91bpm; G6=46.91±9.12bpm), probably because of an increase in cardiac output to uterine perfusion at the end of pregnancy. Normal sinus rhythm was predominant in most of mares of groups G0, G3 and G6, and sinus tachycardia in most of G10 mares. In conclusion, changes in hemodynamics and in cardiac position can influence on the electrocardiogram of pregnant Crioulo mares, but do not cause relevant rhythm or conduction disturbs.(AU)

Evaluation of Persistent Lymphatic Fluid Leakage Using a Strategy of Placing a Drain After Kidney Transplantation: A Statistical Analysis to Assess Its Origin.

OBJECTIVES: Using a strategy of placing a surgical drain after kidney transplantation, the duration of a lymphatic fluid leakage and prevalence of a symptomatic lymphocele were retrospectively analyzed. The risk factors for persistent lymphatic fluid leakage or asymptomatic lymphocele were evaluated using multivariate analysis to estimate the origin of the lymphatic fluid leakage. MATERIALS AND METHODS: Patients with persistent lymphatic fluid leakage and symptomatic lymphocele were defined as those with lymphatic fluid drainage >50 mL for more than 15 days and those who required a percutaneous drainage of the lymphocele, respectively. RESULTS: Persistent lymphatic fluid leakage and symptomatic lymphocele were observed in 40 (16.4%) and 10 (4.1%) of a total of 244 patients, respectively. The maximum durations of lymphatic fluid drainage from the initial drain tube and the second drainage of the symptomatic lymphocele were 48 and 28 days, respectively. Anastomosis of the graft artery to the external iliac artery was an independent risk factor to predict persistent lymphatic fluid leakage or symptomatic lymphocele after kidney transplantation (odds = 2.597, P = .008). CONCLUSION: The findings of the study suggest that the lymphatic fluid originates from the recipient's iliac lymph trunk rather than from the graft kidney.

Regression of gastric de novo diffuse large B-cell lymphoma following Helicobacter pylori eradication: a case report.

We report a case of primary gastric diffuse large B-cell lymphoma (DLBCL), de novo DLBCL without the features of mucosa-associated lymphoid tissue (MALT) lymphoma, which regressed after Helicobacter pylori (HP) eradication. A 27-year-old Japanese female with epigastralgia was revealed to have ulcerated lesions in the angle and antral regions on gastroscopy. Biopsy specimen was consistent with a diagnosis of DLBCL without MALT lymphoma component, indicating de novo development. Her clinical staging on the Lugano system was Stage I. HP was positive on a rapid urease test, and she received HP eradication therapy twice, because the first therapy was not successful. On gastroscopy performed 1 month after the second HP eradication therapy, no ulcerated lesion was noted, and the lymphoma cells had regressed histopathologically. (Acta gastro-enterol. belg., 2016, 79, 367-369A).

Efeitos de dois protocolos de sedação sobre as variáveis bioquímicas em gatos / Effects of two sedation protocols in biochemistry variables in cats

A utilização de protocolos de sedação como auxílio na contenção de felinos para realização de coletas de sangue é de grande importância, porém a utilização de alguns fármacos pode alterar resultados e a interpretação deles. Por outro lado, a contenção física pode gerar intenso estresse, especialmente em felinos, o que também pode interferir nos resultados. Este estudo teve como objetivo avaliar exames de bioquímica clínica sob o uso de contenção física e química em gatos submetidos a dois protocolos de sedação. Foram utilizados 50 gatos, 26 fêmeas e 24 machos, sem raça definida, submetidos a contenção física e, imediatamente após, a dois protocolos de sedação, DB (dexmedetomidina 5µg/kg e butorfanol 0,3mg/kg) e DBC (dexmedetomidina 5µg/kg, butorfanol 0,3mg/kg e cetamina 3mg/kg), aplicados por via intramuscular. Amostras de sangue foram coletadas após a contenção física e, em seguida, após o uso de um dos protocolos de sedação. Foram avaliados: ureia, creatinina, alaninoaminotransferase (ALT), fosfatase alcalina, proteína sérica total (PST), albumina, globulinas, colesterol, triglicérides, cálcio, magnésio e cloretos de amostras de soro, lactato e glicose de amostras de plasma fluoretado. Foi encontrada diferença estatística entre grupos para albumina, triglicérides, PST e colesterol, com maiores valores sendo encontrados no grupo DBC. Entre momentos, houve diferença para colesterol e fosfatase alcalina, com maiores valores no momento contenção física somente no grupo DBC. Já a glicose teve maiores valores após a sedação em ambos os grupos. O estudo revelou que o uso destes protocolos implica restrições para alguns parâmetros bioquímicos aqui estudados e que suas interpretações devem ser avaliadas cuidadosamente.(AU)

The use of sedation protocols to assist in the restraint of cats to perform blood collections is of great importance, but the use of some drugs can alter the results and interpretation. Moreover, the physical restraint may generate intense stress, especially in animals of the feline species, which may also interfere with the results. This study aimed to evaluate examinations of clinical biochemistry in the use of physical restraint and chemistry in cats subjected to two sedation protocols. We used 50 cats, 26 females and 24 males, of mixed-breed, who underwent physical restraint and immediately after underwent two sedation protocols, DB (dexmedetomidine 5µg / kg and 0.3mg butorphanol / kg) and DBC (dexmedetomidine 5µg / kg butorphanol 0.3mg / kg ketamine and 3mg / kg), applied intramuscularly. Blood samples were taken after physical restraint and then after the use of one of the sedation protocols. The following parameters were evaluated: urea, creatinine, alanine aminotransferase (ALT), alkaline phosphatase (ALP), total serum protein (TP), albumin, globulin, cholesterol, triglycerides, calcium, magnesium and chloride in serum samples, and lactate and glucose in fluoride plasma samples. Statistical difference was found between groups for albumin, triglycerides, TP and cholesterol with higher values being found in the DBC group. A statistical difference between moments was found for cholesterol, and ALP with higher values in physical restraint only in the DBC group. Glucose had greater values after sedation for both groups. The study revealed that the use of these protocols implies restrictions on some biochemical parameters studied here, and that their interpretations should be evaluated carefully.(AU)

Perfil bioquímico sérico de equinos clinicamente sadios da raça Campeiro / Serum biochemical profile from clinically healthy Campeiro horses

Amostras de sangue foram obtidas de 138 equinos registrados da raça Campeiro, com idade média de 9,7±5,4 anos, sendo 14 machos (10,15%) e 124 fêmeas (89,85%). Observaram-se valores médios da atividade sérica de GGT: 13,73±4,08 U/L; AST: 246,34±72,87U/L; ALT: 5,13±1,18U/L; FA: 284,32±53,33UI/L; CK: 132,54±72,25U/L; LDH: 511,38±143,65U/L; e das concentrações séricas de ureia: 38,65±12,62mg/dL e de creatinina: 1,24±0,24mg/dL. Os valores médios de AST, FA, ALT, ureia e creatinina foram semelhantes aos propostos na literatura para outras raças. Os valores de CK, GGT e LDH foram superiores aos comumente utilizados como referências. Não houve diferença nas concentrações de nenhum dos componentes séricos avaliados nas diferentes idades analisadas. Maiores valores médios nas concentrações de ureia e menores de creatinina foram observados nas fêmeas em relação aos machos, assim como a maior atividade sérica de FA em fêmeas gestantes em relação às éguas vazias. O perfil bioquímico sérico de equinos sadios da raça Campeiro apresenta variações peculiares que devem ser levadas em consideração na interpretação de exames laboratoriais.(AU)

Blood samples were obtained from 138 equines of the Campeiro breed with mean ages of 9.7±5.4 years, including 14 males (10.15%) and 124 mares (89.85%). Mean values of serum of GGT: 13.73 ± 4.08U/L; AST: 246.34±72.87U/L; ALT 5.13±1.18U/L; FA: 284.32±53.33IU/L; CK: 132.54±72.25U/L; LDH: 511.38±143.65U/L; and serum urea: 38.65±12.62mg/dL and creatinine: 1.24±0.24mg/dL were observed. The mean values of AST, FA, ALT, urea and creatinine were similar to those proposed in the literature for other breeds. The CK values, GGT, and LDH were higher than those commonly used as references. There was no difference in the concentrations of any of the serum components evaluated at different ages analyzed. Further average values in the lower urea concentrations and creatinine were observed in females compared to males, as well as the higher serum activity of FA in pregnant mares in relation to non-pregnant. Serum biochemical profile of healthy horses of the Campeiro breed presents peculiar variations that must be taken into consideration in the interpretation of laboratory tests.(AU)

Diet-induced alteration of fatty acid synthase in prostate cancer progression.

Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the role FASN on HFD-mediated PCa progression remains unclear. We investigated the role of FASN on PCa progression in LNCaP xenograft mice fed with HFD or low-fat diet (LFD), in PCa cells, and in clinical PCa. The HFD promoted tumour growth and FASN expression in the LNCaP xenograft mice. HFD resulted in AKT and extracellular signal-regulated kinase (ERK) activation and 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation. Serum FASN levels were significantly lower in the HFD group (P=0.026) and correlated inversely with tumour volume (P=0.022). Extracellular FASN release was enhanced in the PCa cells with phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) inhibition and AMPK signalling activation. FASN inhibition resulted in decrease of PCa cell proliferation through PI3K/MAPK downregulation and AMPK activation. Furthermore, AMPK activation was associated with FASN downregulation and PI3K/MAPK inactivation. Clinically, high FASN expression was significantly associated with high Gleason scores and advanced pathological T stage. Moreover, FASN expression was markedly decreased in the PCa response to androgen deprivation therapy and chemotherapy. HFD modulates FASN expression, which may be an important mechanism in HFD-associated PCa progression. Furthermore, a critical stimulatory loop exists between FASN and the PI3K/MAPK system, whereas AMPK signalling was associated with suppression. These may offer appropriate targets for chemoprevention and cancer therapy in HFD-induced PCa.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Valproic acid enhances the effect of bone marrow-derived mononuclear cells in a rat ischemic stroke model.

Bone marrow derived mononuclear cell (MNC) transplantation is a potential therapy for ischemic stroke. Here, we hypothesized that valproic acid (VPA) would modulate transplantation effects of MNCs in a rat ischemic stroke model. Male Sprague-Dawley rats were subjected to transient 90min middle cerebral artery occlusion. Infarct volume, neurological outcome, and immunohistological assessments were performed 7 days after ischemia. MNCs injected 6 or 24h but not 48 or 72h after ischemia significantly reduced infarct volume and improved neurological deficits. We then tested whether the therapeutic window of MNC transplantation could be expanded through combination therapy with VPA. MNC transplantation at 48h combined with VPA injection three times at 47, 53, and 72h after ischemia significantly ameliorated infarct volume and neurological deficits compared to a vehicle group. Combination therapy reduced the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, tumor necrosis factor-α-positive cells, and von Willebrand factor-positive cells in the ischemic boundary zone. The number of engrafted MNCs that were fluorescently labeled with PKH 26, on day 7, was significantly higher after combination therapy than after that MNC transplantation alone. Our results demonstrated that combination therapy with VPA enhanced the anti-inflammatory and vasculo-protective effects against endothelial damage following ischemia, and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MNC transplantation. Together, these findings suggest that VPA may be an appropriate partner for cell-based treatment of ischemic stroke.

Preventive effects of hyaluronan from deterioration of gait parameters in surgically induced mice osteoarthritic knee model.

OBJECTIVE: Osteoarthritis (OA) leads to pain and loss of function in affected joints. Gait disturbance results from these symptoms of OA, and gait analysis can be important to evaluate the progression of OA. The purpose of this study was to analyze gait pattern in a rodent model of OA and to assess the effects of intra-articular injection of hyaluronan (IAI-HA) by gait analysis, along with histological evaluation. DESIGN: OA was induced by destabilization of the medial meniscus (DMM) of C57BL/6 mice. IAI-HA started 3 weeks after DMM surgery. Mice were allocated to three groups and were given either 800-kDa HA (800-HA), 6000-kDa HA (6000-HA) or saline. We compared these three groups with a sham group by gait analysis using CatWalk. Histological evaluation was performed to assess articular cartilage changes in the knee joints. RESULTS: Mice injected with 800-HA or 6000-HA showed gait patterns similar to that of the sham mice, while the saline-injected group showed gait disturbances 12 and 16 weeks after DMM surgery. Histological changes in articular cartilage were similar among the 800-HA, 6000-HA and saline-treated groups, demonstrating OA progression throughout the experimental time points. Positive gait-related effects of IAI-HA might occur by its pain relieving effect and/or by preventing contracture. CONCLUSION: IAI-HA prevented gait disturbances in the DMM model, but did not prevent histological changes associated with OA progression.

Blocking of the ATP sensitive potassium channel ameliorates the ischaemia-reperfusion injury in the rat testis.

There is increasing evidence that the effects of administered ATP sensitive potassium (KATP ) channel openers or blockers during ischaemia are still controversial in many organs/tissues. Testicular torsion detorsion which causes ischaemia-reperfusion (IR) injury, cannot be predicted, thus an effective drug should be administered during or after the ischaemia. The aim of this study was to examine whether the administration of KATP channel openers or blockers during ischaemia ameliorates IR injury in the testis. Eight-week-old male Sprague-Dawley rats were subjected to 2 h right testicular ischaemia followed by 24 h reperfusion. The selective mitochondrial (mito) KATP channel blocker, 5-hydroxydecanoate (5-HD) (40 mg/kg), the non-selective KATP channel blocker glibenclamide (5 mg/kg), the selective mito KATP channel opener diazoxide (10 mg/kg) and the non-selective KATP channel opener cromakalim (300 µg/kg) were administered intraperitoneally 15 min prior to the ischaemia or 75 min after the induction of ischaemia. Tissue damage was evaluated by malondialdehyde concentration, myeloperoxidase activity, histological evaluation and TdT-mediated dUTP nick end labelling assay in the testis. There was a significant increase in oxidative stress, neutrophil infiltration, histological damage and apoptosis in the testicular IR model. A significant reduction in the testicular IR injury was observed with the administration of glibenclamide, but not 5-HD, diazoxide or cromakalim during ischaemia. The administration of non-selective KATP channel blocker glibenclamide ameliorated the testicular IR injury. On the other hand, the selective mito KATP channel blocker, 5-HD and KATP channel openers did not reduce the testicular IR injury. These data suggest that blocking of the membrane KATP channel may have a protective effect during the testicular ischaemia. Glibenclamide could be an effective drug to manage the post-ischaemic injury caused by the testicular torsion-detorsion.