Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis

According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient (heterozygous) > Ppp6c wild-type > Ppp6c-deficient (homozygous) tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild-type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild-type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.     

Effects of low-dose irradiation on enhancement of immunity by dendritic cells

Low-doses of irradiation have been reported to have beneficial effects, particularly anti-tumor effects. In this paper, we show the effects of the low-dose irradiation on T cell activation induced by dendritic cells (DCs). DCs, which had been pre-irradiated at 0.02-1.0 Gy from a (137)Cs source, were cultured with allogeneic T cells, and the proliferation of T cells was then examined. The 0.05Gy-pre-irradiated DCs showed the highest proliferation capacity of T cells. The 0.05Gy-irradiation does not augment the expression of major histocompatibility complexes (MHCs) or costimulatory molecules on DCs, as with non-irradiated DCs or 1Gy-irradiated DCs, but does augment the production of IL-2, IL-12 and IFN-gamma DCs. These results suggest that the low-dose irradiation augments T cell-activation capacity through cytokine production by DCs, which might shift na?ve helper T cells to Th1 cells.     

Effectiveness of personal protective equipment in preventing severe acute respiratory syndrome coronavirus 2 infection among healthcare workers

IntroductionInformation on the effectiveness of personal protective equipment (PPE) for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers (HCWs), especially among HCWs with frequent contact with patients with SARS-CoV-2, is limited.MethodsWe conducted a prospective cohort study on 49 HCWs who worked in close contact with patients with SARS-CoV-2 infection. HCWs had blood samples taken every 2 weeks to test for SARS-CoV-2 antibodies using two different types of assay.ResultsForty-nine participants (31 nurses, 15 doctors, 3 other workers) were enrolled. In total, 112 blood samples are obtained from participants. The median work days in 2 weeks was 9 (interquartile range (IQR): 5–10) days. In a single work day, 30 of the 49 participants (61.5%) had contact with patients with suspected or conformed SARS-CoV-2 at least 8 times, and approximately 60% of participants had more than 10 min of contact with a single patient. The median self-reported compliance to PPE was 90% (IQR: 80–100%). Seven participants tested positive for SARS-CoV-2 antibody using enzyme-linked immunosorbent assay (ELISA); however, none were seropositive for SARS-CoV-2 neutralizing antibody, so the positive ELISA results were assumed to be false-positive.ConclusionsThe study provides evidence that appropriate PPE is sufficient to prevent infection amongHCWs. It is necessary to establish a system that provides a stable supply of PPE for HCWs to perform their duties.     

Multicenter,Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma

Introduction

This study compared the efficacy and safety of adjunctive brimonidine tartrate 0.1% ophthalmic solution (brimonidine) and timolol maleate 0.5% ophthalmic solution (timolol) in prostaglandin analogue (PGA)-treated normal-tension glaucoma (NTG), assessing the non-inferiority of brimonidine in terms of intraocular pressure (IOP) reduction.

Methods

In this multicenter, randomized, investigator-masked, parallel-group, clinical study, adjunctive brimonidine or timolol was administered twice daily for 12 weeks in eyes with NTG that had been treated with PGA for at least 90 days and required additional treatment despite an IOP of 16 mmHg or less. IOP was measured on at least three visits before add-on therapy (mean baseline IOP), and at weeks 4, 8, and 12 after adjunctive administration. Systolic/diastolic blood pressure, pulse rate, and adverse events (AEs) were recorded at each visit.

Results

A total of 152 individuals were enrolled and 128 (84.2%) were eligible for efficacy analyses. IOP in both groups at each visit decreased significantly from baseline (P < 0.001). However, the difference in the change from baseline IOP at week 12 between the brimonidine (?1.05 ± 1.81 mmHg) and timolol (?1.41 ± 1.40 mmHg) groups was 0.36 mmHg (95% confidence interval [CI] [?0.21, 0.92]), which exceeded the value of the non-inferiority margin (0.75 mmHg). Baseline systolic/diastolic blood pressure decreased significantly in both groups at certain visits (P < 0.05), while baseline pulse rates decreased significantly in the timolol group (P < 0.001), with no significant differences in the brimonidine group. AE-related treatment discontinuation occurred in 2/71 (2.8%) and 2/75 (2.7%) patients in the brimonidine and timolol groups, respectively.

Conclusion

This study demonstrated an add-on effect of brimonidine to PGAs, although non-inferiority of brimonidine to timolol as adjunctive therapy in PGA-treated NTG in terms of IOP reduction was not observed. Brimonidine was associated with no adverse effects on pulse rate.

Funding

Senju Pharmaceutical Co., Ltd.

Trial registration

UMIN Clinical Trials Registry identifier, UMIN000014810.

     

Outline of the hospital infection control in USA and UK

To establish Infection Control Network System is very important issue to reduce nosocomial infections in the hospital. CDC in United States of America and PHLS in United Kingdom are the core organization in infection control and, since the early 1970s, they have established the infection control system that span the efficient surveillance system, spectrum of hospital practice and clinical activity and provide a means of evaluating the outcome of infection by clinical audit. In many hospitals, the infection control program is well underpinned by a dedicated and knowledgeable infection control team(ICT), in which the infection control doctor(ICD) and infection control practitioner(ICP) involved.     

Ultrasonographic diagnosis of advanced colorectal cancer

We investigated the efficacy of transabdominal ultrasonography for the diagnosis of advanced colorectal cancer. Colonic examination by colonoscopy, barium study, or surgery was carried out in our institution on 1579 patients during the past 5 years. This study focused on 1564 of these patients, 15 who has been diagnosed with colorectal cancer before ultrasound examination having been excluded. The results included 51 ultrasound-positive cases, 9 ultrasound-false-positive cases, 1476 ultrasound-negative cases, and 28 ultrasound-false-negative cases. Sensitivity was 64.6 percent and specificity was 99.6 percent. Of the 28 ultrasound-false-negative cases, the lesion was detected in the ascending colon in 2, in the transverse colon in 6, in the descending colon in 1, in the sigmoid colon in 3, and in the rectum in 16. Obstruction and dilatation suggested colorectal cancer in 3 cases, which were thus classified as ultrasound-negative when no tumors were detected. Sensitivity was investigated by site. Sensitivity was lowest at 30.4 percent in rectal cancer, but was 78.6 percent in colon cancer, exclusive of rectal cancer. Laboratory findings and clinical symptoms which were suggestive of colorectal cancer were used as information before ultrasound examination was performed. Sensitivity of examinations carried out on examinees on whom prior information was available and on those on whom there was no information did not differ significantly. Furthermore, ultrasound was thought to detect approximately 65 percent of advanced colorectal cancers when it was used aggressively to investigate the large intestine. Ultrasound was thus considered effective for detecting advanced colorectal cancer.