Chemoradiation induces upregulation of immunogenic cell death-related molecules together with increased expression of PD-L1 and galectin-9 in gastric cancer.

Surgery alone or combined with chemo- and/or radiation therapy remains the primary treatment for gastric cancer (GC) to date and immunotherapeutic tools such as monoclonal antibodies are only slowly being implemented. This is partly due to the fact that the immune microenvironment in GC during chemoradiation and other treatment modalities is still poorly understood. 7 gastric cancer (GC) cell lines were tested for their response to chemoradiation using 5-FU in combination with X-ray irradiation. We conducted flow cytometric analysis to determine the cells' ability to undergo immunogenic cell death (ICD) and their expression of the two immunosuppressive proteins programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9). We evaluated the overall immunogenicity of two cell lines (MKN7, MKN74) in co-culture experiments with human monocyte-derived dendritic cells (Mo-DCs). Chemoradiation induces distinct responses in different GC cell lines. We observe ICD in vitro in all tested GC cell lines in the form of calreticulin (CRT) translocation to the plasma membrane. As a resistance mechanism, these cells also upregulated Gal-9 and PD-L1. Mo-DC maturation experiments showed that GCs provoked the maturation of Mo-DCs after chemoradiation in vitro. The addition of α-PD-L1 blocking antibody further enhanced the immunogenicity of these cells while improving DC viability. Blocking Tim-3, as the main receptor for Gal-9, had no such effect. Our findings suggest that the benefits of chemoradiation can substantially depend on tumor subtype and these benefits can be offset by induced immune evasion in GC. Combination treatment using checkpoint inhibitors could potentially lead to enhanced immune responses and yield better patient outcomes.

Evaluation of a WASH intervention demonstrates the potential for improved hygiene practices in Hiri District, Central Province

Water, sanitation and hygiene (WASH) interventions aim to improve health outcomes through provision of safe water supplies and improved sanitation facilities, while also promoting better hygiene practices in communities. Population Services International introduced a WASH intervention project in the Hiri District, Central Province in May 2012. Shortly after its introduction we conducted a survey to determine the uptake of the intervention and gauge its impact. We invited 400 households to participate in the study, which consisted of a questionnaire for the head of the household. A total of 395 questionnaires were completed: 314 from households that had participated in the WASH intervention and 81 that had not (controls). Results demonstrated that improved water sources were not routinely used, with a high dependence on well and surface water. While self-reported handwashing was common, use of soap was not common. Treatment of water inside the house was common in the intervention group (95%), compared to 49% in the non-WASH group. The study indicates that people in the Hiri District are supportive of a WASH intervention, with good uptake of some aspects of the intervention. The sustainability of the intervention remains unknown. Targetted interventions focusing on community priorities might be beneficial in the future.

Nuclear Thimet oligopeptidase is coexpressed with oestrogen receptor alpha in hypothalamic cells and regulated by oestradiol in female mice.

Thimet oligopeptidase (EC 3.4.24.15; also called EP24.15 and TOP; referred to here as TOP) is a neuropeptidase involved in the regulation of several physiological functions including reproduction. Among its substrates is gonadotrophin-releasing hormone (GnRH), an important hypothalamic hormone that regulates the synthesis and release of oestradiol and facilitates female sexual behaviour. Using immunohistochemistry, we found that TOP is expressed in the nucleus of cells throughout the female mouse brain, and in high levels in steroid-sensitive regions of the hypothalamus, which is consistent with previous findings in male rats. Furthermore, dual-label immunofluorescence revealed that TOP and oestrogen receptor alpha (ERalpha) coexpress in several reproductively-relevant brain regions, including the medial preoptic area (mPOA), arcuate nucleus (ARC), ventrolateral portion of the ventromedial hypothalamic nucleus (VMNvl) and the midbrain central grey (MCG). Previous studies in rats have shown that oestradiol decreases hypothalamic TOP levels or activity, possibly potentiating the effects of GnRH. In the present study, analysis by immunohistochemistry revealed that oestradiol decreased TOP immunoreactivity in the VMNvl, whereas no differences were detected in the mPOA, ARC or median eminence. Overall, the present findings indicate that TOP is coexpressed with ERalpha, and oestradiol regulates TOP expression in a brain region-specific manner in female mice, providing neuroanatomical evidence that TOP may function in reproductive physiology and/or behaviour.

Ceftazidime versus a combination of amikacin and ticarcillin in the treatment of severe infections.

Hospital patients with severe gram-negative bacterial infections were randomly assigned to treatment with ceftazidime (2 gm every eight or 12 hours) or a combination of amikacin (500 mg every 12 hours) and ticarcillin (3 gm every six or eight hours). The clinical and bacteriological responses to treatment were satisfactory in most of the patients in both treatment groups. Clinical cure was achieved in 18 of the 20 patients treated with ceftazidime and in 17 of the 20 treated with amikacin-ticarcillin. The bacterial eradication rate was 19 of 21 pathogens in the ceftazidime group and 17 of 20 pathogens in the amikacin-ticarcillin group.