Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Correlation between Objective Measures of Sun Exposure and Self-Reported Sun Protective Behavior and Attitudes in Predominantly Hispanic Youth.

Melanoma incidence is increasing, with poor prognosis cases growing faster in California Hispanics than in non-Hispanic whites. Ultraviolet Radiation (UVR) exposure as a child has been found to disproportionately increase the risk of melanoma. To determine correlates of UVR exposure in this high-risk population, we conducted a study in predominately Hispanic 4th and 5th grade classrooms in Los Angeles County, a high UVR environment, during the spring. To address potential reporting bias, electronic UV dosimeters were utilized to objectively measure the association between UVR exposure and constructs (acculturation, sun protective behavior and knowledge, family interventions) obtained on baseline questionnaires (n = 125). Tanning attitude (wanting to get a tan) was associated with lower median time spent outside (1.73 min versus 22.17, AUC 82.08, Sensitivity 0.78, Specificity 0.73) and standard erythemal dose (SED) on weekends, but positively associated with sun protective knowledge. Sun protective knowledge and family discussion of sunscreen were also inversely associated with objectively measured time outside. Students spent a median 30.61 (IQR 19.88) minutes outside per day (SED 0.30, IQR 0.20), with only 35.70% of it occurring in nonschool hours. We determined the majority of UVR exposure in this population occurs at school, providing valuable guidance for future interventions.

Cumulative menstrual months and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities Study.

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends = .0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in nonobese (BMI <30 kg/m2 ) women and a significant inverse association in obese women (OR per 50 CMM = 0.56, 95% CI 0.37-0.87, Ptrend  = .03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM = 1.33, P = .07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer.

A convergence of rRNA and mRNA quality control pathways revealed by mechanistic analysis of nonfunctional rRNA decay.

Eukaryotes possess numerous quality control systems that monitor both the synthesis of RNA and the integrity of the finished products. We previously demonstrated that Saccharomyces cerevisiae possesses a quality control mechanism, nonfunctional rRNA decay (NRD), capable of detecting and eliminating translationally defective rRNAs. Here we show that NRD can be divided into two mechanistically distinct pathways: one that eliminates rRNAs with deleterious mutations in the decoding site (18S NRD) and one that eliminates rRNAs containing deleterious mutations in the peptidyl transferase center (25S NRD). 18S NRD is dependent on translation elongation and utilizes the same proteins as those participating in no-go mRNA decay (NGD). In cells that accumulate 18S NRD and NGD decay intermediates, both RNA types can be seen in P-bodies. We propose that 18S NRD and NGD are different observable outcomes of the same initiating event: a ribosome stalled inappropriately at a sense codon during translation elongation.

Chapter 12. Analysis of nonfunctional ribosomal RNA decay in Saccharomyces cerevisiae.

Mature rRNA are normally extremely stable in rapidly growing cells. However, studies show that some mature rRNA in Saccharomyces cerevisiae are, in fact, turned over quite rapidly by the nonfunctional rRNA decay (NRD) pathway. NRD eliminates the RNA component of mature but defective ribosomal subunits and ribosomes. NRD was discovered using rDNA reporter plasmids to express and track the fate of rRNA containing mutations in functionally important regions of the ribosome. This chapter outlines some of the available rDNA reporter plasmids that can be used to study NRD and describes assays to test for functionality and stability of rRNA in yeast.

A late-acting quality control process for mature eukaryotic rRNAs.

Ribosome biogenesis is a multifaceted process involving a host of trans-acting factors mediating numerous chemical reactions, RNA conformational changes, and RNA-protein associations. Given this high degree of complexity, tight quality control is likely crucial to ensure structural and functional integrity of the end products. We demonstrate that ribosomal RNAs (rRNAs) containing individual point mutations, in either the 25S peptidyl transferase center or 18S decoding site, that adversely affect ribosome function are strongly downregulated in Saccharomyces cerevisiae. This downregulation occurs via decreased stability of the mature rRNA contained in fully assembled ribosomes and ribosomal subunits. Thus, eukaryotes possess a quality-control mechanism, nonfunctional rRNA decay (NRD), capable of detecting and eliminating the rRNA component of mature ribosomes.

Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells.

OBJECTIVE: Interferon-gamma (IFN-gamma), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN-gamma in GAD. METHODS: Wild-type (WT), IFN-gamma-/-, or recombination-activating-gene-1-/- (RAG-1-/-; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN-gamma expression by infiltrating cells. RESULTS: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-gamma expression by both infiltrating T cells and macrophages. No GAD developed in IFN-gamma-/- or in RAG-1-/- hosts, nor was any IFN-gamma expression evident. RAG-1-/- hosts receiving naïve WT or IFN-gamma-/- T cells (10(7)) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1-/- recipients yielded GAD, with associated IFN-gamma expression by the transferred T cells and the host macrophages. Transfer of IFN-gamma-/- T cells induced neither GAD nor host macrophage IFN-gamma expression. CONCLUSIONS: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-gamma plays a critical role in GAD pathogenesis.

Human metapneumovirus in children tested at a tertiary-care hospital.

BACKGROUND: Respiratory infections are the leading cause of outpatient visits in the United States, but the etiology of many of these infections is unknown. Human metapneumovirus (hMPV) is a recently discovered virus that causes respiratory infections. METHODS: Respiratory specimens obtained from patients

Detection of multiple macrolide- and lincosamide-resistant strains of Streptococcus pyogenes from patients in the Boston area.

Macrolide (including erythromycin and azithromycin) and lincosamide (including clindamycin) antibiotics are recommended for treatment of penicillin-allergic patients with Streptococcus pyogenes pharyngitis. Resistance to erythromycin in S. pyogenes can be as high as 48% in specific populations in the United States. Macrolide and lincosamide resistance in S. pyogenes is mediated by several different genes. Expression of the erm(A) or erm(B) genes causes resistance to erythromycin and inducible or constitutive resistance to clindamycin, respectively, whereas expression of the mef(A) gene leads to resistance to erythromycin but not clindamycin. We studied the resistance of S. pyogenes to erythromycin and clindamycin at an urban tertiary-care hospital. Of 196 sequential isolates from throat cultures, 15 (7.7%) were resistant to erythromycin. Three of these were also constitutively resistant to clindamycin and had the erm(B) gene. Five of the erythromycin-resistant isolates were resistant to clindamycin upon induction with erythromycin and had the erm(A) gene. The remaining seven erythromycin-resistant isolates were susceptible to clindamycin even upon induction with erythromycin and had the mef(A) gene. Pulsed-field gel electrophoresis analysis and emm typing demonstrated that the erythromycin-resistant S. pyogenes comprised multiple strains. These results demonstrate that multiple mechanisms of resistance to macrolide and lincosamide antibiotics are present in S. pyogenes strains in the United States.

Tumor necrosis factor receptor -1 and -2 double deficiency reduces graft arterial disease in murine cardiac allografts.

Graft arterial disease (GAD) remains the leading cause of long-term solid organ allograft failure. Tumor necrosis factor (TNF) promotes multiple aspects of allograft rejection via binding to type 1 (p55) and type 2 (p75) receptors. We used TNF type 1 receptor deficient (TNFR1KO), type 2 receptor deficient (TNFR2KO) and receptor double-deficient (TNFRDKO) mice to assess the relative roles of TNFR in acute rejection and GAD. Heterotopic cardiac transplantation was performed between C57BL/6 (B/6) and Balb/c (B/c) mice (total allomismatches) to assess the effects on graft survival; B/6 and Bm12 mice (class II mismatches) were used to assess the effects on GAD 8 weeks after transplantation. We found that graft survival in the total allomismatch combinations was the same regardless of TNFR status. In class II mismatches, wild-type (WT) combinations showed severe GAD, and GAD was not diminished when WT hearts were transplanted into TNFRDKO hosts. TNFR1KO donors or TNFR2KO donors had GAD comparable to WT donors, however, GAD was significantly diminished in B/6 TNFRDKO donor hearts. We conclude that both p55 and p75 signals on donor vascular wall cells are involved in the development of GAD, and either TNFR is capable of mediating a response that will culminate in GAD.