Single-cell Profiling Uncovers a Muc4-Expressing Metaplastic Gastric Cell Type Sustained by Helicobacter pylori-driven Inflammation.

Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation. Significance: Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

Flame retardant exposures in California early childhood education environments.

Infants and young children spend as much as 50h per week in child care and preschool. Although approximately 13 million children, or 65% of all U.S. children, spend some time each day in early childhood education (ECE) facilities, little information is available about environmental exposures in these environments. We measured flame retardants in air and dust collected from 40 California ECE facilities between May 2010 and May 2011. Low levels of six polybrominated diphenyl ether (PBDE) congeners and four non-PBDE flame retardants were present in air, including two constituents of Firemaster 550 and two tris phosphate compounds [tris (2-chloroethyl) phosphate (TCEP) and tris (1,3-dichloroisopropyl) phosphate (TDCIPP)]. Tris phosphate, Firemaster 550 and PBDE compounds were detected in 100% of the dust samples. BDE47, BDE99, and BDE209 comprised the majority of the PBDE mass measured in dust. The median concentrations of TCEP (319 ng g(-1)) and TDCIPP (2265 ng g(-1)) were similar to or higher than any PBDE congener. Levels of TCEP and TDCIPP in dust were significantly higher in facilities with napping equipment made out of foam (Mann-Whitney p-values<0.05). Child BDE99 dose estimates exceeded the RfD in one facility for children<3 years old. In 51% of facilities, TDCIPP dose estimates for children<6 years old exceeded age-specific "No Significant Risk Levels (NSRLs)" based on California Proposition 65 guidelines for carcinogens. Given the overriding interest in providing safe and healthy environments for young children, additional research is needed to identify strategies to reduce indoor sources of flame retardant chemicals.

Prometheus payment model: application to hip and knee replacement surgery.

The Prometheus Payment Model offers a potential solution to the failings of the current fee-for-service system and various forms of capitation. At the core of the Prometheus model are evidence-informed case rates (ECRs), which include a bundle of typical services that are informed by evidence and/or expert opinion as well as empirical data analysis, payment based on the severity of patients, and allowances for potentially avoidable complications (PACs) and other provider-specific variations in payer costs. We outline the methods and findings of the hip and knee arthroplasty ECRs with an emphasis on PACs. Of the 2076 commercially insured patients undergoing hip arthroplasty in our study, PAC costs totaled $7.8 million (14% of total costs; n = 699 index PAC stays). Similarly, PAC costs were $12.7 million (14% of total costs; n = 897 index PAC stays) for 3403 patients undergoing knee arthroplasty. By holding the providers clinically and financially responsible for PACs, and by segmenting and quantifying the type of PACs generated during and after the procedure, the Prometheus model creates an opportunity for providers to focus on the reduction of PACs, including readmissions, making the data actionable and turn the waste related to PAC costs into potential savings.

Fractionated stereotactic radiotherapy for acoustic neuromas: preservation of function versus size.

For larger acoustic neuromas the preservation of cranial nerve function following radiosurgery remains a challenge. Fractionated stereotactic radiotherapy (FSR) for acoustic neuromas offers both higher total tumour dose (Gy) and potential sparing of the facial motor, sensory and auditory cranial nerves. Eighty consecutive patients (45 M, 35 F) (age 56.8+/-1.7 years) received FSR for AN and have a median follow up of 1.1 years. A prospective schedule permitted increased fractionation vs. size. For FSR 70 patients having AN < 3.0 cm in diameter had 5 daily fractions of 5 Gy (25 Gy total) and 10 patients having AN > or = 3 cm had 10 daily fractions of 3 Gy (30 Gy total). All treatments were prescribed to the 80% isodose and given via the dedicated 10 MeV accelerator. For both the larger and smaller AN, the percentage decrease in volume was similar. No tumour increased in size, no patient developed facial weakness and hearing was preserved. Using size-dependent fractionation, FSR may result in both tumour control and preservation of normal cranial nerve functions for both large and small AN.

Fractionated stereotactic radiotherapy for acoustic neuromas.

Fractionated stereotactic radiotherapy (FSR) for acoustic neuromas offers both higher tumor dose and potential sparing of the facial and auditory cranial nerve functions. Eighty consecutive patients (45 males and 35 females; age 56.8 +/- 1.7 years) received FSR for acoustic neuromas and had a median follow-up of 2.9 years (range 2.3-6.5 years). For FSR, 70 patients had 5 daily fractions of 5 Gy (25 Gy total) and 10 patients had 10 daily fractions of 3 Gy (30 Gy total). Volume decreased by an average of 18%. No tumor increased in size, no patient developed facial weakness, and hearing was preserved.

Fractionated stereotactic radiotherapy for acoustic neuromas.

PURPOSE: When compared with radiosurgery, fractionated stereotactic radiotherapy for acoustic neuroma (AN) offers escalation of the tumor dose and potential sparing of auditory and facial nerve functions. METHODS AND MATERIALS: Between 1996 and 2001, 249 consecutive patients have received fractionated stereotactic radiotherapy for AN. One hundred twenty-five patients had follow-up >1 year and were the subject of this report. A noninvasive, repeat-fixation mask allowed simulation by way of spiral CT. Two distinct schedules for total dose and fractionation were used. For an AN <3.0 cm in diameter (volume 1.4 +/- 0.2 cm(3)), patients received 25 Gy given in 5 consecutive daily fractions of 5 Gy (111 patients), and for ANs >or=3.0 cm (volume 8.1 +/- 1.2 cm(3)), patients received 30 Gy given in 10 fractions of 3 Gy (14 patients). RESULTS: The percentage of decrease in tumor size was 12% +/- 2% (range 0-100%) vs. 13% +/- 3% (range 0-38%) for the 25 Gy vs. 30 Gy regimens, respectively. No patient had growth of the AN or developed facial weakness. Two patients developed transient decreases in facial sensation. The rates of hearing preservation were similar for the larger and smaller tumors. CONCLUSION: Fractionated stereotactic radiotherapy may preserve normal function and control both small and large ANs.