Helicobacter pylori CagA oncoprotein interacts with SHIP2 to increase its delivery into gastric epithelial cells

Chronic infection with Helicobacter pylori cagA‐positive strains is causally associated with the development of gastric diseases, most notably gastric cancer. The cagA‐encoded CagA protein, which is injected into gastric epithelial cells by bacterial type IV secretion, undergoes tyrosine phosphorylation at the Glu‐Pro‐Ile‐Tyr‐Ala (EPIYA) segments (EPIYA‐A, EPIYA‐B, EPIYA‐C, and EPIYA‐D), which are present in various numbers and combinations in its C‐terminal polymorphic region, thereby enabling CagA to promiscuously interact with SH2 domain‐containing host cell proteins, including the prooncogenic SH2 domain‐containing protein tyrosine phosphatase 2 (SHP2). Perturbation of host protein functions by aberrant complex formation with CagA has been considered to contribute to the development of gastric cancer. Here we show that SHIP2, an SH2 domain‐containing phosphatidylinositol 5′‐phosphatase, is a hitherto undiscovered CagA‐binding host protein. Similar to SHP2, SHIP2 binds to the Western CagA‐specific EPIYA‐C segment or East Asian CagA‐specific EPIYA‐D segment through the SH2 domain in a tyrosine phosphorylation‐dependent manner. In contrast to the case of SHP2, however, SHIP2 binds more strongly to EPIYA‐C than to EPIYA‐D. Interaction with CagA tethers SHIP2 to the plasma membrane, where it mediates production of phosphatidylinositol 3,4‐diphosphate [PI(3,4)P₂]. The CagA‐SHIP2 interaction also potentiates the morphogenetic activity of CagA, which is caused by CagA‐deregulated SHP2. This study indicates that initially delivered CagA interacts with SHIP2 and thereby strengthens H. pylori‐host cell attachment by altering membrane phosphatidylinositol compositions, which potentiates subsequent delivery of CagA that binds to and thereby deregulates the prooncogenic phosphatase SHP2.     

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.     

Effects of hyaluronic acid on the release of proteoglycan from the cell matrix in rabbit chondrocyte cultures in the presence and absence of cytokines

Objective. To investigate the effects of hyaluronic acid (HA) on the release of proteoglycan by cultured rabbit chondrocytes. Methods. Articular cartilage chondrocytes were isolated from the knee joints of New Zealand white rabbits. Proteoglycan synthesis after incubation with HA was determined by measuring ³⁵S-sulfate incorporation. Cells incubated with HA were labeled with ³H-glucosamine and applied to a Sepharose CL-2B column. After incubation of confluent cells with ³⁵S-sulfate and then with HA in various concentrations in the presence or absence of cytokines, proteoglycan release from the cell matrix layer was measured. Results. HA (M_r 3 × 10⁵ to 19 × 10⁵), at 10 μg/ml to 1 mg/ml, had little effect on the incorporation of ³⁵S-sulfate or ³H-glucosamine into cartilage matrix proteoglycans, or on the hydrodynamic size of proteoglycan monomers, in rabbit chondrocyte cultures. However, at 10–1,000 μg/ml, HA suppressed the release of ³⁵S-proteoglycans from the cell matrix layer into the medium in the presence and absence of interleukin-1, tumor necrosis factor α, or basic fibroblast growth factor. Conclusion. These results suggest that HA is a potent inhibitor of the displacement of matrix proteoglycan into culture medium.     

Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis

Omalizumab is used for the treatment of persistent severe allergic asthma in adults and children. However, some patients remain symptomatic even after omalizumab treatment. In bronchial asthma, chronic inflammation of the bronchial wall causes thickening of the airway wall, resulting from irreversible airway remodeling. Progression of airway remodeling causes airflow obstruction, leading to treatment resistance. We report three Japanese children with severe asthma who had a poor response to omalizumab treatment. They had a long period of inadequate management of asthma before initiating omalizumab. Even after omalizumab treatment, their symptoms persisted, and the parameters of spirometry tests did not improve. We hypothesized that omalizumab was less effective in these patients because airway wall remodeling had already progressed. We retrospectively evaluated the bronchial wall thickness using a three-dimensional bronchial wall analysis with chest computed tomography. The bronchial wall thickness was increased in these cases compared with six responders. Progressed airway wall thickness caused by airway remodeling may be associated with a poor response to omalizumab in children with severe asthma.     

Functional and oncological outcomes after retropharyngeal node dissection for papillary thyroid carcinoma

European Archives of Oto-Rhino-Laryngology - Papillary thyroid carcinoma frequently metastasizes to central and lateral neck lymph nodes, but metastasis to retropharyngeal lymph nodes (RPLN) is...     

The Impact of COVID-19 on Academic Cancer Clinical Trials in Canada and the Initial Response from Cancer Centers

The COVID-19 pandemic resulted in temporary holds placed on new trial startups, patient recruitment and follow up visits for trials which contributed to major disruptions in cancer center trial unit operations. To assess the impact, the Canadian Cancer Clinical Trials Network (3CTN) members participated in regional meetings and a survey to understand the impact of the pandemic to academic cancer clinical trials (ACCT) activity, cancer trial unit operations and supports needed for post-pandemic recovery. Trial performance and recruitment data collected from 1 April 2020–31 March 2021 was compared to the same period in previous years. From 1 April–30 June 2020, patient recruitment decreased by 67.5% and trial site activations decreased by 81% compared to the same period in 2019. Recovery to reopening and recruitment of ACCTs began after three months, which was faster than initially projected. However, ongoing COVID-19 impacts on trial unit staffing and operations continue to contribute to delayed trial activations, lower patient recruitment and may further strain centers’ capacity for participation in academic-sponsored trials.     

Amenamevir,a novel helicase–primase inhibitor,for treatment of herpes zoster: A randomized,double‐blind,valaciclovir‐controlled phase 3 study

Amenamevir is a potent helicase–primase inhibitor and a novel class of antiviral agent other than nucleoside compounds, such as aciclovir, valaciclovir and famciclovir. This study is the first randomized, double‐blind, valaciclovir‐controlled phase 3 study to evaluate the efficacy and safety of amenamevir in Japanese patients with herpes zoster when treated within 72 h after onset of rash. A total of 751 patients were randomly assigned to receive either amenamevir 400 mg or 200 mg p.o. once daily or valaciclovir 1000 mg three times daily (daily dose, 3000 mg) for 7 days. The primary efficacy end‐point was the proportion of cessation of new lesion formation by day 4 (“day 4 cessation proportion”). The day 4 cessation proportions for amenamevir 400 and 200 mg and valaciclovir were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively. Non‐inferiority of amenamevir 400 mg to valaciclovir was confirmed by a closed testing procedure. Days to cessation of new lesion formation, complete crusting, healing, pain resolution and virus disappearance were evaluated as secondary end‐points. No significant differences were observed in any of the treatment groups. Amenamevir 400 and 200 mg were well tolerated as well as valaciclovir. The proportions of patients who experienced drug‐related adverse events were 10.0% (25/249), 10.7% (27/252) and 12.0% (30/249) with amenamevir 400 and 200 mg and valaciclovir, respectively. In conclusion, amenamevir 400 mg appears to be effective and well tolerated for treatment of herpes zoster in immunocompetent Japanese patients.     

Frequency of Treponema pallidum invasion into cerebrospinal fluid in primary or secondary early-stage syphilis

Frequency of Treponema pallidum invasion into cerebrospinal fluid (CSF) has not been clear at this present. Since it is impossible to culture T. pallidum in vitro at this present, we need molecular based-approach to detect it in CSF. Additionally, neurosyphilis is usually a late sequela, however it might result in asymptomatic neurosyphilis even at primary or secondary syphilis. This study was to reveal the frequency of T. pallidum invasion into CSF especially at primary or secondary syphilis with polymerase chain reaction (PCR) test.All patients were visited the Aichi Medical University Hospital or Izumi ladies' clinic between 2016 and 2017. Clinical CSF samples were collected from patients with early and late stages of syphilis. The PCR was done using primers targeting the tpN47gene.CSF samples were collected from 9 patients (4 patients with primary syphilis, 3 with secondary syphilis, and 1 early latent syphilis and 1 with late latent syphilis). PCR showed positive reaction in 2 of 7 (28.6%) primary and secondary syphilis patients, in 1 of 1 (100%) early latent syphilis patients, and in 1 of 1 (100%) late latent syphilis patients.Despite its lack of sensitivity for use alone as a diagnostic test, this PCR test should be preferred for the diagnosis of neurosyphilis. Because, T. pallidum was detected in the 28.6% CSF of patients at primary and secondary syphilis, which indicated that they invade the central nervous system from the early stages of infection. However, studies in a larger population are required to confirm these preliminary results.     

Robot-Assisted Radical Prostatectomy for Potential Cancer Control in Patients with Metastatic Prostate Cancer

Recently, cytoreductive prostatectomy for metastatic prostate cancer (mPCa) has been associated with improved oncological outcomes. This study was aimed at evaluating whether robot-assisted radical prostatectomy (RARP) as a form of cytoreductive prostatectomy can improve oncological outcomes in patients with mPCa. We conducted a retrospective study of twelve patients with mPCa who had undergone neoadjuvant therapy followed by RARP. The endpoints were biochemical recurrence-free survival, treatment-free survival, and de novo metastasis-free survival. At the end of the follow-up period, none of the enrolled patients had died from PCa. The 1- and 2-year biochemical recurrence-free survival rates were 83.3% and 66.7%, respectively, and treatment-free survival rates were 75.0% and 56.3%, respectively. One patient developed de novo bone metastases 6.4 months postoperatively, and castration-resistant prostate cancer 8.9 months postoperatively. After RARP, the median duration of recovery of urinary continence was 5.2 months. One patient had severe incontinence (>2 pads/day) 24 months postoperatively. RARP may be a treatment option in patients with mPCa who have achieved a serum prostate-specific antigen level < 0.2 ng/mL, and present without new lesions on imaging.