Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL).

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Endocrine islet ß-cell subtypes with differential function are derived from biochemically distinct embryonic endocrine islet progenitors that are regulated by maternal nutrients.

Endocrine islet b cells comprise heterogenous cell subsets. Yet when/how these subsets are produced and how stable they are remain unknown. Addressing these questions is important for preventing/curing diabetes, because lower numbers of b cells with better secretory function is a high risk of this disease. Using combinatorial cell lineage tracing, scRNA-seq, and DNA methylation analysis, we show here that embryonic islet progenitors with distinct gene expression and DNA methylation produce b-cell subtypes of different function and viability in adult mice. The subtype with better function is enriched for genes involved in vesicular production/trafficking, stress response, and Ca2+-secretion coupling, which further correspond to differential DNA methylation in putative enhancers of these genes. Maternal overnutrition, a major diabetes risk factor, reduces the proportion of endocrine progenitors of the b-cell subtype with better-function via deregulating DNA methyl transferase 3a. Intriguingly, the gene signature that defines mouse b-cell subtypes can reliably divide human cells into two sub-populations while the proportion of b cells with better-function is reduced in diabetic donors. The implication of these results is that modulating DNA methylation in islet progenitors using maternal food supplements can be explored to improve b-cell function in the prevention and therapy of diabetes.

Mitigating COVID-19 Risk and Vaccine Hesitancy Among Underserved African American and Latinx Individuals with Mental Illness Through Mental Health Therapist-Facilitated Discussions.

BACKGROUND: Underserved ethnic minorities with psychiatric disorders are at an increased risk of COVID-19. This study aims to examine the effectiveness of one-to-one counseling on COVID-19 vaccination and vaccination readiness among underserved African American and Latinx individuals with mental illnesses and adult caregivers of children with mental illness. METHODS: Through an academic-community partnered collaboration, a multidisciplinary and culturally sensitive training on COVID-19 was co-developed and delivered to 68 therapists from January to March 2021. Mental health clients and their caregivers were recruited to participate in pre- and post-intervention surveys to evaluate the impact of the intervention on their perceptions of COVID-19 public health guidelines, testing, and vaccination. Mental health therapists delivered four lessons of the COVID-19 educational intervention with 254 clients from March to June 2021, when vaccine availability was widely available. Of those clients, we collected 180 baseline and 115 follow-up surveys. The main outcome was the uptake in COVID-19 vaccine. RESULTS: There was a positive shift in participant vaccine acceptance and receptivity. Pre-intervention survey shows that only 56% of adult clients and 48% of caregivers had indicated a likelihood of getting the vaccine for themselves at baseline. Post-intervention documented that more than 57% of each group had been vaccinated, with another 11-15% of the unvaccinated individuals reporting that they were somewhat or very likely to get the vaccine. CONCLUSION: This study demonstrated that multidisciplinary academic-community and theoretical-based educational intervention delivered by mental health therapists is an effective strategy in increasing COVID-19 vaccine acceptance and reducing the negative impact and disruption that COVID-19 caused in the daily life of mental health patients and caregivers.

Injury-Induced Cellular Plasticity Drives Intestinal Regeneration.

The epithelial lining of the intestine, particularly the stem cell compartment, is affected by harsh conditions in the luminal environment and also is susceptible to genotoxic agents such as radiation and chemotherapy. Therefore, the ability for intestinal epithelial cells to revert to a stem cell state is an important physiological damage response to regenerate the intestinal epithelium at sites of mucosal injury. Many signaling networks involved in maintaining the stem cell niche are activated as part of the damage response to promote cellular plasticity and regeneration. The relative contribution of each cell type and signaling pathway is a critical area of ongoing research, likely dependent on the nature of injury as well as the regional specification within the intestine. Here, we review the current understanding of the multicellular cooperation to restore the intestinal epithelium after damage.

The Effect of Thiol Structure on Allyl Sulfide Photodegradable Hydrogels and their Application as a Degradable Scaffold for Organoid Passaging.

Intestinal organoids are useful in vitro models for basic and translational studies aimed at understanding and treating disease. However, their routine culture relies on animal-derived matrices that limit translation to clinical applications. In fact, there are few fully defined, synthetic hydrogel systems that allow for the expansion of intestinal organoids. Here, an allyl sulfide photodegradable hydrogel is presented, achieving rapid degradation through radical addition-fragmentation chain transfer (AFCT) reactions, to support routine passaging of intestinal organoids. Shear rheology to first characterize the effect of thiol and allyl sulfide crosslink structures on degradation kinetics is used. Irradiation with 365 nm light (5 mW cm-2 ) in the presence of a soluble thiol (glutathione at 15 × 10-3 m), and a photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate at 1 × 10-3 m), leads to complete hydrogel degradation in less than 15 s. Allyl sulfide hydrogels are used to support the formation of epithelial colonies from single intestinal stem cells, and rapid photodegradation is used to achieve repetitive passaging of stem cell colonies without loss in morphology or organoid formation potential. This platform could support long-term culture of intestinal organoids, potentially replacing the need for animal-derived matrices, while also allowing systematic variations to the hydrogel properties tailored for the organoid of interest.

Utilization of cryopreserved sperm cells based on the indication for storage.

Purpose: Cryopreservation of sperm from human semen has been available since the 1950s. The actual utilization of available cryopreservation technology has been infrequently reported. We set out to examine the utilization and outcomes of cryopreserved sperm cells based on the indication for storage. Materials and Methods: A dataset was developed from retrospective review. The purposes for cryopreservation, eventual utilization, and outcomes of use for insemination were recorded. The types of utilization were accumulated as proportions for different purposes. The timing for use of samples for insemination procedures was evaluated using survival statistics. The frequency of patients arranging to destroy samples was also reported. Results: From September 1988 through March 2015, 1442 samples were cryopreserved. Samples were cryopreserved for four primary purposes: infertility treatments focused on intrauterine insemination (IUI) or in vitro fertilization/intracellular injection (IVF/ICSI), for fertility preservation related to cancer treatment, or prior to military deployment. Total utilization rates were 19.3%. Samples cryopreserved for IUI were more likely to be used (64.3%), while samples cryopreserved as backup for IVF/ICSI were more likely to be destroyed (29.8%). Pregnancy rates varied based on the indication and ART used. Pregnancies per cycle were 35% for IVF/ICSI and were 10% for IUI. Conclusions: Cryopreservation of sperm is a valuable and underutilized resource, particularly amongst male cancer patients. This technology can facilitate infertility treatments based on a variety of indications, including deployment-a patient cohort unique to our dataset.

Time trends for bacterial species and resistance patterns in semen in patients undergoing evaluation for male infertility.

Semen from asymptomatic men who are being evaluated as male partners in interfile couples have been reported to contain a variety of bacteria. Longitudinal studies of the variation of these bacteria over time and their resistance patterns have not been commonly reported. At our institution, residues from semen samples are routinely evaluated for bacteria, including antibiotic sensitivity profiles. We set out to profile the changes in semen bacteria and antibiotic resistance at our institution over time. A total of 72 semen isolates were examined for type of bacteria and sensitivity to a panel of antibiotics. The results were divided into two separate 5-year intervals (the first beginning in 2006, the second in 2011) and compared. The majority of bacteria were skin flora, with Streptococcus and Staphylococcus being the most prevalent. The resistance data for these two pathogens showed minimal statistically significant difference between the two time periods, although the Staphylococcus species did show a trend toward increasing resistance, suggesting that antibiotics currently used in sperm cell preparations may need to be varied.

Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function.

Retroviral integrase catalyses the integration of viral DNA into host target DNA, which is an essential step in the life cycle of all retroviruses. Previous structural characterization of integrase-viral DNA complexes, or intasomes, from the spumavirus prototype foamy virus revealed a functional integrase tetramer, and it is generally believed that intasomes derived from other retroviral genera use tetrameric integrase. However, the intasomes of orthoretroviruses, which include all known pathogenic species, have not been characterized structurally. Here, using single-particle cryo-electron microscopy and X-ray crystallography, we determine an unexpected octameric integrase architecture for the intasome of the betaretrovirus mouse mammary tumour virus. The structure is composed of two core integrase dimers, which interact with the viral DNA ends and structurally mimic the integrase tetramer of prototype foamy virus, and two flanking integrase dimers that engage the core structure via their integrase carboxy-terminal domains. Contrary to the belief that tetrameric integrase components are sufficient to catalyse integration, the flanking integrase dimers were necessary for mouse mammary tumour virus integrase activity. The integrase octamer solves a conundrum for betaretroviruses as well as alpharetroviruses by providing critical carboxy-terminal domains to the intasome core that cannot be provided in cis because of evolutionarily restrictive catalytic core domain-carboxy-terminal domain linker regions. The octameric architecture of the intasome of mouse mammary tumour virus provides new insight into the structural basis of retroviral DNA integration.

Role of the neutrophil chemorepellent soluble dipeptidyl peptidase IV in decreasing inflammation in a murine model of arthritis.

OBJECTIVE: To determine whether an intraarticular injection of the neutrophil chemorepellent dipeptidyl peptidase IV (DPPIV; CD26) can attenuate inflammation and decrease the severity of arthritis in a murine model. METHODS: DBA/1 mice were immunized with type II collagen/Freund's complete adjuvant to produce collagen-induced arthritis (CIA). On day 25 postimmunization, recombinant human DPPIV (rhDPPIV) or phosphate buffered saline was injected intraarticularly, and arthritis severity scores were recorded 3 times per week. The hind legs of mice in both groups were fixed, decalcified, paraffin embedded, and sectioned. Pathologic scores for inflammation and neutrophil infiltration were recorded on a scale of 1-8, and the number of neutrophils was determined by morphometric cell counts. In addition, Mac-2-positive macrophages and articular damage were assessed using anti-Mac-2 antibodies and histologic staining, respectively. RESULTS: Injection of rhDPPIV reduced the mean score of arthritis severity in mice with CIA. DPPIV treatment reduced the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue, and also decreased neutrophil and macrophage infiltration. CONCLUSION: A localized injection of the neutrophil chemorepellent DPPIV reduces inflammation and the severity of the disease in a murine model of arthritis.

Pathogenesis of Systemic Sclerosis.

Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

SUGAR: spotting undiagnosed glucose abnormal results--a new protocol to increase postpartum testing among women with gestational diabetes mellitus.

OBJECTIVE: Over 70% of women with gestational diabetes mellitus (GDM) will develop diabetes mellitus (DM), but only 30% follow through with the recommended postpartum oral glucose tolerance testing (OGTT). HbA1c is approved to diagnose DM, and combined with a fasting plasma glucose it can identify 93% of patients with dysglycemia. We tested the hypothesis that a single blood draw to assess for dysglycemia at the postpartum visit could improve testing rates compared with those required to obtain an OGTT at an outside laboratory. STUDY DESIGN: Prospective cohort study of all women with GDM who delivered between July 2010 and December 2011. When insurance status required testing at an outside laboratory an OGTT was ordered, when insurance allowed testing at our center a random sugar and HbA1c were drawn at the postpartum visit (SUGAR Protocol). RESULTS: Of the 40 women, 36 attended a postpartum visit. In the SUGAR arm, 19 of 19 (100%) were tested versus 9 of 17 (53%) in the OGTT arm; relative risk of testing was 1.9 (95% confidence interval, 1.2-3.0). 36% were glucose intolerant. CONCLUSION: This pilot study found that an in-office testing model doubled the rate of postpartum testing in this clinic population, and was reasonably sensitive at detecting dysglycemia.

Evolving epidemiologic trends in nonclear cell renal cell cancer: an analysis of the California Cancer Registry.

OBJECTIVE: To evaluate the California Cancer Registry in order to define nonclear cell renal cell cancer (RCC) clinical features and outcomes, identify prognostic variables, and generate hypotheses for further study. METHODS: Patients with invasive RCC tumors in the California Cancer Registry from 1998 to 2009 (n = 38,251) were analyzed, of which 4483 (11.7%) were of the nonclear cell type. Baseline clinical demographics and tumor characteristics were collected. Primary outcome measures were 3-year cause-specific survival (CSS) and overall survival (OS). RESULTS: Of 4483 nonclear cell RCC cases, 3304 (73.7%) were diagnosed between 2004 and 2009. Histologic distribution was as follows: papillary 63.9%, chromophobe 33.6%, and "other" 2.5% (including medullary and collecting duct tumors). Univariate analysis showed that chromophobe histology, female sex, and higher socioeconomic status were associated with significantly better OS and CSS. Patients in the later era (2004-2009) appeared to have better OS. Multivariate analysis showed the following to be independently associated with outcomes (hazard ratios shown for CSS and OS, respectively): chromophobe (0.48, 0.56; P <.001), medullary/collecting duct (2.99, 2.42; P <.001), no nephrectomy (2.84, 3.18; P <.001), regional stage (5.84, 1.98; P <.001), distant stage (25.7, 7.67; P <.001), and non-Hispanic blacks (1.5, P = .006; 1.25, P = .03). CONCLUSION: This large registry analysis demonstrated emerging epidemiologic trends in this uncommon RCC subset. Clinical variables associated with CSS and OS were identified that can potentially inform the design of future clinical trials in nonclear cell RCC.

Rational design of fatty acid amide hydrolase inhibitors that act by covalently bonding to two active site residues.

The design and characterization of α-ketoheterocycle fatty acid amide hydrolase (FAAH) inhibitors are disclosed that additionally and irreversibly target a cysteine (Cys269) found in the enzyme cytosolic port while maintaining the reversible covalent Ser241 attachment responsible for their rapid and initially reversible enzyme inhibition. Two α-ketooxazoles (3 and 4) containing strategically placed electrophiles at the C5 position of the pyridyl substituent of 2 (OL-135) were prepared and examined as inhibitors of FAAH. Consistent with the observed time-dependent noncompetitive inhibition, the cocrystal X-ray structure of 3 bound to a humanized variant of rat FAAH revealed that 3 was not only covalently bound to the active site catalytic nucleophile Ser241 as a deprotonated hemiketal, but also to Cys269 through the pyridyl C5-substituent, thus providing an inhibitor with dual covalent attachment in the enzyme active site. In vivo characterization of the prototypical inhibitors in mice demonstrates that they raise endogenous brain levels of FAAH substrates to a greater extent and for a much longer duration (>6 h) than the reversible inhibitor 2, indicating that the inhibitors accumulate and persist in the brain to completely inhibit FAAH for a prolonged period. Consistent with this behavior and the targeted irreversible enzyme inhibition, 3 reversed cold allodynia in the chronic constriction injury model of neuropathic pain in mice for a sustained period (>6 h) beyond that observed with the reversible inhibitor 2, providing effects that were unchanged over the 1-6 h time course monitored.

A 9-year-old boy with chronic urticaria and progressive spondyloarthritis.

A 9-year-old African American boy presented with chronic urticaria and progressive spondyloarthritis. Laboratory tests were abnormal for persistently positive antinuclear antibodies and undetectable total hemolytic complement (CH50) despite normal levels of complement C2, C3, and C4. Ultimately, further testing revealed an underlying deficiency in the immune system that may be associated with autoimmune disease and thus have a bearing on the patient's urticaria and spondyloarthritis. This is a unique presentation of a rare disease and underscores the importance of evaluating for systemic disease in the workup of chronic urticaria.

20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo.

CONTEXT: There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D(3) was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D(3)] and 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), and 17,20,23(OH)(3)D(3). OBJECTIVES: Because 20(OH)D(3) is noncalcemic (nontoxic) in vivo at very high doses, we evaluated its antifibrogenic activities both in vitro and in vivo. Because it is further metabolized by CYP11A1, we also tested preclinical utilities of its hydroxyderivatives, especially 20,23(OH)(2)D(3). DESIGN: Human dermal fibroblasts from scleroderma and normal donors were used to test the efficiency of hydroxyvitamin D derivatives in inhibiting TGF-ß1-induced collagen and hyaluronan synthesis and inhibiting cell proliferation. The in vivo activity of 20(OH)D(3) was tested using bleomycin-induced sclerosis in C57BL/6 mice. RESULTS: 20(OH)D(3) and 20,23(OH)(2)D(3) inhibited TGF-ß1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)(2)D(3) in cultured human fibroblasts. Also, 20(OH)D(3), 20,23(OH)(2)D(3), and 1,25(OH)(2)D(3) suppressed TGF-ß1-induced expression of COL1A2, COL3A1, and hyaluronan synthase-2 mRNA, indicating that they regulate these matrix components at the transcriptional level. 20(OH)D(3), 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), and 17,20,23(OH)(3)D(3) inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)(2)D(3), with 20(OH)D(2) being less active and 1α(OH)D(3) being almost inactive. 20,23(OH)(2)D(3) at 3 µg/kg had no effect on serum Ca(++) or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D(3) markedly suppressed fibrogenesis in mice given sc bleomycin as demonstrated by total collagen content and hematoxylin and eosin staining of skin biopsies. CONCLUSIONS: 20(OH)D(3) is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.

Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta).

Aged individuals are more susceptible to infections due to a general decline in immune function broadly referred to as immune senescence. While age-related changes in the adaptive immune system are well documented, aging of the innate immune system remains less well understood, particularly in nonhuman primates. A more robust understanding of age-related changes in innate immune function would provide mechanistic insight into the increased susceptibility of the elderly to infection. Rhesus macaques have proved a critical translational model for aging research, and present a unique opportunity to dissect age-dependent modulation of the innate immune system. We examined age-related changes in: (i) innate immune cell frequencies; (ii) expression of pattern recognition receptors (PRRs) and innate signaling molecules; (iii) cytokine responses of monocytes and dendritic cells (DC) following stimulation with PRR agonists; and (iv) plasma cytokine levels in this model. We found marked changes in both the phenotype and function of innate immune cells. This included an age-associated increased frequency of myeloid DC (mDC). Moreover, we found toll-like receptor (TLR) agonists lipopolysaccharide (TLR4), fibroblast stimulating ligand-1 (TLR2/6), and ODN2006 (TLR7/9) induced reduced cytokine responses in aged mDC. Interestingly, with the exception of the monocyte-derived TNFα response to LPS, which increased with age, TNFα, IL-6, and IFNα responses declined with age. We also found that TLR4, TLR5, and innate negative regulator, sterile alpha and TIR motif containing protein (SARM), were all expressed at lower levels in young animals. By contrast, absent in melanoma 2 and retinoic acid-inducible gene I expression was lowest in aged animals. Together, these observations indicate that several parameters of innate immunity are significantly modulated by age and contribute to differential immune function in aged macaques.

Characterization of inhibitory T cells induced by an analog of type II collagen in an HLA-DR1 humanized mouse model of autoimmune arthritis.

INTRODUCTION: We used DR1 transgenic mice and covalently linked DR1 multimers to characterize analog-specific inhibitory T cells in collagen-induced arthritis (CIA). Because of the low numbers of antigen-specific T cells in wild-type mice, functional T-cell studies in autoimmune arthritis have been challenging. The use of T-cell receptor (TCR) transgenic mice has provided useful information, but such T cells may not represent the heterogeneous T-cell response that occurs in natural settings. Our focus was to develop tools to identify and characterize the population of immunoregulatory T cells induced in wild-type mice by an analog peptide of CII259-273, which contains amino acid substitutions at positions 263 (N) and 266 (D) (analog peptide A12). METHODS: DR1 multimers, developed by loading empty class II molecules with exogenous peptide, provide a method for visualizing antigen-specific T cells with flow cytometry. However, the low binding avidity of A12 for the major histocompatibility complex (MHC) made this strategy untenable. To overcome this problem, we generated DR1 multimers in which the analog peptide A12 was covalently linked, hoping that the low-avidity analog would occupy enough binding clefts to allow detection of the responsive T cells. RESULTS: Staining with the tetramer revealed that A12-specific T cells were readily detectable at 10 days after immunization. These CD4(+) T cells are a highly selective subset of the TCR repertoire and have a limited clonality. Analysis of cytokine expression showed that cells detected by tetramer (A12) expressed primarily suppressive cytokines (interleukin-4 (IL-4) and IL-10) in response to collagen, compared with control cells. Although they did not express Fox-p3, they were extremely effective in preventing and suppressing inflammatory arthritis. CONCLUSIONS: In summary, our studies showed that the use of covalently linked multimers allows characterization of analog-specific T cells that are otherwise difficult to detect. The suppressive character of the analog-specific T-cell response suggests that these cells attenuate autoimmunity and differ significantly in phenotype from the inflammatory T cells predominantly found in arthritic joints. Such reagents will become powerful tools to study T-cell responses in RA patients in upcoming clinical trials.

Using community-based participatory research (CBPR) to develop a community-level HIV prevention intervention for Latinas: a local response to a global challenge.

INTRODUCTION AND BACKGROUND: The arsenal of interventions to reduce the disproportionate rates of HIV and sexually transmitted disease (STD) infection among Latinos in the United States lags behind what is available for other populations. The purpose of this project was to develop an intervention that builds on existing community strengths to promote sexual health among immigrant Latinas. METHODS: Our community-based participatory research (CBPR) partnership engaged in a multistep intervention development process. The steps were to (1) increase Latina participation in the existing partnership, (2) establish an intervention team, (3) review the existing sexual health literature, (4) explore health-related needs and priorities of Latinas, (5) narrow priorities based on what is important and changeable, (6) blend health behavior theory with Latinas' lived experiences, (7) design an intervention conceptual model, (8) develop training modules and (9) resource materials, and (10) pretest and (11) revise the intervention. RESULTS: The MuJEReS intervention contains five modules to train Latinas to serve as lay health advisors (LHAs) known as "Comadres." These modules synthesize locally collected data with other local and national data, blend health behavior theory with the lived experiences of immigrant Latinas, and harness a powerful existing community asset, namely, the informal social support Latinas provide one another. CONCLUSION: This promising intervention is designed to meet the sexual health priorities of Latinas. It extends beyond HIV and STDs and frames disease prevention within a sexual health promotion framework. It builds on the strong, preexisting social networks of Latinas and the preexisting, culturally congruent roles of LHAs.

A fatal presentation of dermatomyositis with facial swelling.

Juvenile dermatomyositis (JDM) is the most common inflammatory autoimmune myopathy in children. Most common presentations consist of heliotrophic rash and/or gottron's papules in addition to proximal muscle weakness. A typical presentations have been reported. We present a 13-year-old African American male who presented with a two-week history of bilateral periorbital edema that was unresponsive to glucocorticoids. He had elevated transaminases but no detectable muscle weakness. A muscle biopsy was consistent with juvenile dermatomyositis. This case highlights the need to consider dermatomyositis in cases of facial swelling and the use of aggressive immunosuppressive therapies due to its associated vasculopathies.

Epidemiologic trends in renal cell carcinoma in the cytokine and post-cytokine eras: a registry analysis of 28,252 patients.

UNLABELLED: Advances in the targeted treatment of renal cell cancer (RCC) have shown improvements in survival in clinical trials and have largely replaced cytokine therapies as the standard of care. However it is unclear if these advances have translated to the general RCC population. We present a retrospective study of a large clinical cancer registry that demonstrates statistically significant improvements in survival in cancer patients, but the causes of this improvement are difficult to determine because of many confounders. BACKGROUND: Before 2004, advanced renal cell cancer (RCC) therapy consisted primarily of cytokines such as interferon and/or interleukin-2. Subsequently, randomized trials of targeted therapies have shown a survival benefit, leading to the approval of several new agents since 2004. Whether the survival benefit seen in highly selected patients accrued to these trials has already translated to the general RCC patient population is unclear. To explore this, a large RCC patient registry was evaluated for changes in outcome between the cytokine (1998-2003) and post-cytokine (2004-2007) eras. METHODS: Data from the California Cancer Registry (CCR), a population-based cancer surveillance system, was used to retrospectively analyze 28,252 patients with RCC diagnosed between 1998 and 2007. Inter-era differences in clinical variables-including year of diagnosis, histologic characteristics, age, sex, race, stage, nephrectomy status, overall survival (OS), and cause-specific survival (CSS)-were assessed. Univariate and multivariate Cox models were used. RESULTS: Crude 3-year OS (68.2% vs. 74.6%; 2P < .001) and CSS (78.1% vs. 82.3%; 2P < .001) were significantly higher in the post-cytokine era. In multivariate analysis, the 3 strongest predictors for improved survival were localized disease (hazard ratio [HR], 18.1; 95% confidence interval [CI], 16.6-19.6), nephrectomy (HR, 2.87; 95% CI, 2.68-3.08), and clear cell histologic type (HR, 1.33; 95% CI, 1.22-1.44). CONCLUSIONS: In this analysis of a large RCC registry, there was an apparent increase in crude OS and CSS in the post-cytokine era compared with the cytokine era. Insufficient follow-up time in the post-cytokine era and a higher proportion of localized disease in that era confound the possibility of benefit derived from targeted therapies. Longer follow-up for patients treated in the post-cytokine era is necessary for a more robust comparison of long-term OS.