Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Parental Attitudes Toward Breastfeeding: Their Association with Feeding Outcome at Hospital Discharge

Abstract: Background : A woman chooses to breastfeed for many reasons. Recent research, however, suggests that parental attitudes toward breastfeeding are stronger predictors of infant feeding choice than commonly cited sociodemographic factors. The objective of the current study was to compare the infant feeding attitudes of expectant couples, and to determine to what degree their individual attitudes during early pregnancy were predictive of the method of infant feeding at discharge from hospital. Methods : A convenience sample of pregnant women (gestational age 8–12 weeks), who were attending maternity clinics in Glasgow, Scotland, in 2000, completed the 17‐item Iowa Infant Feeding Attitude Scale (IIFAS), together with their partners. Results : The IIFAS was completed by 108 expectant couples. At discharge from hospital 49.1 percent of women were exclusively breastfeeding, and 50.9 percent were exclusively formula‐feeding. A woman's total infant feeding attitude score was significantly correlated with her partner's score(r = 0.67, p < 0.001). There was no difference in the infant feeding attitudes of formula‐feeding couples(p = 0.987), but breastfeeding women tended to be more supportive of breastfeeding than their partners(p = 0.022). Maternal, but not paternal, infant feeding attitude was a significant predictor of the choice of feeding method (OR = 1.16 95% CI = 1.09–1.24). Conclusions : Infant feeding attitudes tended to be shared by expectant couples. Maternal infant feeding attitude was a better predictor of feeding choice than were demographic factors. Paternal attitudes were not found to be independently associated with feeding choice. Identification of women with neutral infant feeding attitudes using the IIFAS may be an effective way of targeting interventions at those women who are most likely to be receptive to such programs.     

Mouse Sperm Rosette: Assembling During Epididymal Transit,in vitro Disassemble,and Oligosaccharide Participation in the Linkage Material

In many mammals, sperm associations had been observed, but not in the mouse. In this work, mouse sperm rosettes are morphologically described inside the epididymis and during its dissolution in a culture medium. Also characterized are the saccharides present in the linking material. Sperm association and other epididymal actions are supported by sperm during epididymal transit and are verified at the caudal region, suggesting a relation between epididymal transit and sperm maturation. In drops of epididymal content obtained from distal (cauda), but not from proximal (caput and corpus) regions; dissolved in culture medium, rosettes appear to be 10 to 15 motile sperm joined by their heads. After 3 min, sperm progressively detach, disassembling the rosette. These structures are studied by several techniques, including optic, electronic (scanning electron microscopy and transmission electron microscopy), and video microscopy. At the ultrastructural level, a dense network of electron‐dense material was observed between sperm heads, joining them. Based on previous works in rat, several lectins were used to characterize the type of saccharides present in this linking material. To avoid the contact between sperm and epididymal fluid from distal region—that probably exerts an influence on sperm association—a ligature was placed between caput and corpus. This epididymal content isolated from caput did not display any rosettes after 28 days. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.     

The role of nitrinergic connections in central cardiovascular responses mediated by physostigmine infused into posterior hypothalamus

In the last few decades, cholinergic connections located into posterior hypothalamus (PH) have been implicated in the central regulation of blood pressure (BP). Here we investigated the role of nitric oxide (NO) in the blood pressure response elicited by infusion of physostigmine into PH of normotensive rats. In freely moving rats, physostigmine (60-200 nM) produced a dose- and time-dependent elevation of BP which was antagonized by the antimuscarinic drug scopolamine (60 nM) and by L-NAME (100 microM), an inhibitor of NO synthase, both infused into the same site. In contrast, L-arginine (L-Arg; 100 microM), the precursor of NO, and glyceryltrinitrate (GTN; 140 nM), an NO donor, infused into the PH did not affect physostigmine-related pressor response. In rats pre-treated with Escherichia coli lipopolisaccharide (LPS; 0.5 microg i.p. 24h beforehand), however, scopolamine, L-Arg and GTN produced a decrease of BP, an effect antagonized by L-NAME. This suggests that NO only slightly modulates physostigmine-related pressor response elicited into PH of LPS-untreated rats. In contrast, the release of large amounts of NO generated by pre-treating rats with LPS, down-regulates cholinergic connections located at the PH, thus contributing in the central dysregulation of BP which can be found when high circulating endotoxin levels may occur.     

Identification and Subcellular Localization of Neuronal Calcium Sensor-1 (NCS-1) in Human Neutrophils and HL-60 Cells

Secretion in neutrophils is thought to be regulated in different ways for the different granule types. Specific granules are endowed with proteins which are related to docking and fusion events and are absent on azurophilic granules. Furthermore, even if secretion of content from all neutrophil granules is a Ca(2+)-dependent process, a higher concentration of cytosolic calcium is required for azurophilic than for specific granule secretion. In this paper we show that human neutrophils and promyelocitic cells express neuronal calcium sensor-1 (NCS-1), a calcium binding protein involved in exocytosis in various cell types. Both mRNA and protein were found in mature cells and precursors. NCS-1 is shown to be mainly associated with azurophilic granules and, therefore could play an instrumental role in the calcium-dependent secretion of azurophilic granules.     

The effect of omalizumab on nasal allergic inflammation

BACKGROUND: In sensitized patients, coupling between IgE and FcepsilonRI receptors on mast cells leads to release of proinflammatory mediators and a subsequent influx of inflammatory cells to the affected organ. Omalizumab (Xolair; formerly rhuMAb-E25) binds to circulating IgE, thus preventing induction of the allergic process. OBJECTIVE: We investigated the effect of treatment with omalizumab on seasonal allergic rhinitis and related changes in inflammatory cell numbers in nasal biopsy specimens. METHODS: Patients were randomized to treatment with omalizumab or placebo before the pollen season; the treatment was started and continued during season. Symptoms and use of medication were recorded, and blood samples and nasal biopsy specimens were obtained before and during season. Immunocytochemistry was performed on biopsy sections through use of the following antibodies: anti-CD4, CD8 (T lymphocytes), EG2, and anti-eosinophil peroxidase (eosinophils), anti-tryptase (mast cells), human neutrophil lipocalin (neutrophils), and antibodies against IgE and FcepsilonRI. RESULTS: During the season, blood eosinophils increased in placebo-treated patients but not in omalizumab-treated patients (P =.01); the difference between the treatment groups was significant (P =.04). Free IgE in serum decreased significantly (P =.0002) in omalizumab-treated patients but not in placebo-treated patients; the difference between the groups was significant (P =.0001). In nasal biopsy specimens, the number of eosinophil peroxidase-positive staining cells increased in the placebo-treated patients (P =.003) but not in the actively treated patients during the season; the difference between the groups was significant (P =.0001). The number of IgE(+) staining cells decreased significantly in the omalizumab group during the season in comparison with the placebo group (P =.04). CONCLUSION: The clinical benefit of treatment with omalizumab is associated with an anti-inflammatory effect on cellular markers in blood and nasal tissue.     

Morphine and methadone impact on human phagocytic physiology

Human subjects submitted to treatment with morphine show a severe depression of phagocytosis, killing properties and superoxide production both of their polymorphonuclear leukocytes and monocytes. Polymorphonuclear leukocyte adherence, chemotaxis, random migration, myeloperoxidase content, lysozyme content and lymphocyte Rosette E formation were poorly influenced. Methadone-treated subjects show a similar effect at phagocytic level but far less evident. These results confirm those previously found in animals and reinforce the evidence of a depressive role of morphine on phagocytic physiology.     

Objective stress monitoring based on wearable sensors in everyday settings

Abstract

Monitoring people’s stress levels has become an essential part of behavioural studies for physical and mental illnesses conducted within the biopsychosocial framework. There have been several stress assessment studies in laboratory-based controlled settings. However, the results of these studies do not always translate effectively to an everyday context. The current state of wearable sensor technology allows us to develop systems measuring the physiological signals reflecting stress 24/7 while capturing the context. In this paper, we present a stress monitoring system that provides objective daily stress measurements in everyday settings based on three physiological signals: electrocardiogram (ECG), photoplethysmogram (PPG), and galvanic skin response (GSR) using Shimmer3 ECG, Shimmer3 GSR+, and Empatica E4 wearable sensors. We perform controlled stress assessment experiments on 17 participants in which we successfully detect stress with a 94.55% accuracy for 10-fold cross-validation and an 85.71% accuracy for subject-wise cross-validation. In everyday settings, the system assesses stress with an 81.82% accuracy. We also examine whether motion artefacts affect stress assessment and filter the low-confidence readings to minimise false alarms.     

The interleukin-13 production by peripheral blood T cells from atopic dermatitis patients does not require CD2 costimulation

BACKGROUND: Although allergic mechanisms appear to be important, the pathogenesis of both extrinsic and intrinsic forms of atopic dermatitis (AD) is unknown. METHODS: We compared the cytokine production of peripheral blood mononuclear cells of extrinsic AD (EAD) and intrinsic AD (IAD) patients and normal control individuals after stimulation with anti-CD3 and/or anti-CD28 monoclonal antibodies (mAbs) in the presence or absence of anti-CD2-blocking mAb. The cytokine production was measured by immunoassays in supernatants of 24-hour cultures. RESULTS: EAD patients showed a decreased capacity to synthesize interferon gamma and granulocyte-macrophage colony-stimulating factor upon anti-CD3 mAb stimulation as compared with IAD patients. Both EAD and IAD patients demonstrated an increased production of interleukin (IL)-5 and IL-13. As expected, interferon gamma, granulocyte-macrophage colony-stimulating factor, and IL-5 levels were reduced in the presence of anti-CD2-blocking mAbs. CD28 costimulation restored the release in cultures with anti-CD2 mAbs added, suggesting that CD2 and CD28 have redundant functions in T cell activation and subsequent cytokine production. Strikingly, the IL-13 production was not blocked by anti-CD2 mAbs and also not increased by agonistic anti-CD28 mAb, in particular within the EAD patient group. CONCLUSION: The signalling pathway initiated by the T cell receptor complex leading to increased IL-13 production in AD patients appears to be highly sensitive and is largely independent on CD2 costimulatory signals.