: Despite many efforts, regulation of skin and hair pigmentation is still not fully understood. This article focuses mainly on controversial aspects in pigment cell biology which have emerged over ...the last decade. The central role of tyrosinase as the key enzyme in initiation of melanogenesis has been closely associated with the 6BH4 dependent phenylalanine hydroxylase (PAH) and tyrosine hydroxylase isoform I (THI) providing evidence for an old concept of the three enzyme theory in the initiation of the pigmentation process. In this context, it is noteworthy that intracellular L‐phenylalanine uptake and turnover to L‐tyrosine via PAH is vital for substrate supply of THI and tyrosinase. While PAH acts in the cytosol of melanocytes, THI and tyrosinase are sitting side by side in the melanosomal membrane. THI at low pH provides L‐3,4‐hydroxyphenylalanine L‐DOPA which in turn is required for activation of met‐tyrosinase. After an intramelanosomal pH change, possibly by the p‐protein, has taken place, tyrosinase is subject to control by 6/7BH4 and the proopiomelanocortin (POMC) peptides α‐MSH melanocyte stimulating hormone and β‐MSH in a receptor independent manner. cAMP is required for the activation of microphthalmia‐associated transcription factor to induce expression of tyrosinase, for transcription of THI and for activation of PAH. The redundancy of the cAMP signal is discussed. Finally, we propose a novel mechanism involving H2O2 in the regulation of tyrosinase via p53 through transcription of hepatocyte nuclear factor 1α which in turn can also affect the POMC response.
We suggest that firms' national institutional environments alter the logic of alliance partner selection and associated knowledge acquisition. We posit that cross-national variations in corporatist ...institutional structures (which reflect differences in underlying cooperative norms) influence the relative importance that firms place on a prospective partner's social value (evidenced from the partner's connectedness with members of its industry) and technological value (reflected in the technological complementarity and novelty of the partner's knowledge). We expect that as prospective partners' technological value increases, the probability of alliance formation increases the most for firms residing in less corporatist countries. Likewise, as prospective partners' social value increases, the probability of alliance formation increases the most for firms in more corporatist countries. We further argue that norms regarding knowledge acquisition within an alliance vary across countries, with deliberate learning approaches serving as the norm in less—not more—corporatist settings. We expect that such differences will lead to more immediate interpartner knowledge acquisition in less corporatist environments. Analysis of a longitudinal cross-national data set of alliances in the emergent fuel cell technology industry supports our arguments. Our findings highlight the significance of particular national institutions in specific organizational domains and the complementarity between institutional theory and other strategic resource-based perspectives in the context of interorganizational alliances.
Background
Hispanic populations in the United States experience numerous barriers to care access. It is unclear how cancer screening disparities between Hispanic and non‐Hispanic White individuals ...are explained by access to care, including having a usual source of care and health insurance coverage.
Methods
A secondary analysis of the 2019 National Health Interview Survey was conducted and included respondents who were sex‐ and age‐eligible for cervical (n = 8316), breast (n = 6025), or colorectal cancer screening (n = 11,313). The proportion of ever screened and up to date for each screening type was compared. Regression models evaluated whether controlling for reporting a usual source of care and type of health insurance (public, private, none) attenuated disparities between Hispanics and non‐Hispanic White individuals.
Results
Hispanic individuals were less likely than non‐Hispanic White individuals to be up to date with cervical cancer screening (71.6% vs. 74.6%) and colorectal cancer screening (52.9% vs. 70.3%), but up‐to‐date screening was similar for breast cancer (78.8% vs. 76.3%). Hispanic individuals (vs. non‐Hispanic White) were less likely to have a usual source of care (77.9% vs. 86.0%) and more likely to be uninsured (23.6% vs. 7.1%). In regressions, insurance fully attenuated cervical cancer disparities. Controlling for both usual source of care and insurance type explained approximately half of the colorectal cancer screening disparities (adjusted risk difference: −8.3 –11.2 to –4.8).
Conclusion
Addressing the high rate of uninsurance among Hispanic individuals could mitigate cancer screening disparities. Future research should build on the relative successes of breast cancer screening and investigate additional barriers for colorectal cancer screening.
Plain language summary
This study uses data from a national survey to compare cancer screening use those who identify as Hispanic with those who identify as non‐Hispanic White.
Those who identify as Hispanic are much less likely to be up to date with colorectal cancer screening than those who identify as non‐Hispanic White, slightly less likely to be up to date on cervical cancer screening, and similarly likely to receive breast cancer screening.
Improving insurance coverage is important for health equity, as is further exploring what drives higher use of breast cancer screening and lower use of colorectal cancer screening.
Hispanic populations in the United States experience numerous barriers to care access. Using a secondary analysis of survey data demonstrated that the magnitude of screening disparities for Hispanic individuals varies by screening type, and that addressing the high rate of uninsurance among Hispanic individuals could help mitigate cancer screening disparities.
Mosquito saliva is a mix of numerous proteins that are injected into the skin while the mosquito searches for a blood meal. While mosquito saliva is known to be immunogenic, the salivary components ...driving these immune responses, as well as the types of immune responses that occur, are not well characterized. We investigated the effects of one potential immunomodulatory mosquito saliva protein, sialokinin, on the human immune response. We used flow cytometry to compare human immune cell populations between humanized mice bitten by sialokinin knockout mosquitoes or injected with sialokinin, and compared them to those bitten by wild-type mosquitoes, unbitten, or saline-injected control mice. Humanized mice received 4 mosquito bites or a single injection, were euthanized after 7 days, and skin, spleen, bone marrow, and blood were harvested for immune cell profiling. Our results show that bites from sialokinin knockout mosquitoes induced monocyte and macrophage populations in the skin, blood, bone marrow, and spleens, and primarily affected CD11c- cell populations. Other increased immune cells included plasmacytoid dendritic cells in the blood, natural killer cells in the skin and blood, and CD4+ T cells in all samples analyzed. Conversely, we observed that mice bitten with sialokinin knockout mosquitoes had decreased NKT cell populations in the skin, and fewer B cells in the blood, spleen, and bone marrow. Taken together, we demonstrated that sialokinin knockout saliva induces elements of a TH1 cellular immune response, suggesting that the sialokinin peptide is inducing a TH2 cellular immune response during wild-type mosquito biting. These findings are an important step towards understanding how mosquito saliva modulates the human immune system and which components of saliva may be critical for arboviral infection. By identifying immunomodulatory salivary proteins, such as sialokinin, we can develop vaccines against mosquito saliva components and direct efforts towards blocking arboviral infections.
Background
For women with hormone receptor positive breast cancer, long‐term endocrine therapy (ET) can greatly reduce the risk of recurrence, yet adherence is low‐ particularly among traditionally ...underserved populations.
Methods
The Carolina Breast Cancer Study oversampled Black and young women (<50 years of age). Participants answered an ET‐specific medication adherence questionnaire assessing reasons for non‐adherence. We used principal factor analysis to identify latent factors describing ET non‐adherence. We then performed multivariable regression to determine clinical and demographic characteristics associated with each ET non‐adherence factor.
Results
1,231 women were included in analysis, 59% reported at least one barrier to ET adherence. We identified three latent factors which we defined as: habit ‐ challenges developing medication‐taking behavior; tradeoffs ‐ high perceived side effect burden and medication safety concerns; and resource barriers ‐ challenges related to cost or accessibility. Older age (50+) was associated with less reporting of habit (Adjusted Risk Ratio (aRR) 0.5495% CI: 0.43‐0.69 and resource barriers (aRR 0.660.43‐0.997), but was not associated with tradeoff barriers. Medicaid‐insured women were more likely than privately‐insured to report tradeoff (aRR:1.53 1.10‐2.13) or resource barriers (aRR:4.432.49‐6.57). Black race was associated with increased reporting of all factors (habit: aRR 1.291.09‐1.53; tradeoffs: 1.321.09‐1.60, resources: 1.651.18‐2.30).
Conclusion
Barriers to ET adherence were described by three distinct factors, and strongly associated with sociodemographic characteristics. Barriers to ET adherence appear inadequately addressed for younger, Black, and publicly‐insured breast cancer survivors. These findings underscore the importance of developing multi‐faceted, patient‐centered interventions that address a diverse range of barriers to ET adherence.
This study sought to characterize racial and ethnic disparities in cervical cancer screening and follow-up of abnormal findings across 3 U.S. healthcare settings.
Data were from 2016 to 2019 and were ...analyzed in 2022, reflecting sites within the Multi-level Optimization of the Cervical Cancer Screening Process in Diverse Settings & Populations Research Center, part of the Population-based Research to Optimize the Screening Process consortium, including a safety-net system in the southwestern U.S., a northwestern mixed-model system, and a northeastern integrated healthcare system. Screening uptake was evaluated among average-risk patients (i.e., no previous abnormalities) by race and ethnicity as captured in the electronic health record, using chi-square tests. Among patients with abnormal findings requiring follow-up, the proportion receiving colposcopy or biopsy within 6 months was reported. Multivariable regression was conducted to assess how clinical, socioeconomic, and structural characteristics mediate observed differences.
Among 188,415 eligible patients, 62.8% received cervical cancer screening during the 3-year study period. Screening use was lower among non-Hispanic Black patients (53.2%) and higher among Hispanic (65.4%,) and Asian/Pacific Islander (66.5%) than among non-Hispanic White patients (63.5%, all p<0.001). Most differences were explained by the distribution of patients across sites and differences in insurance. Hispanic patients remained more likely to screen after controlling for a variety of clinical and sociodemographic factors (risk ratio=1.14, CI=1.12, 1.16). Among those receiving any screening test, Black and Hispanic patients were more likely to receive Pap-only testing (versus receiving co-testing). Follow-up from abnormal results was low for all groups (72.5%) but highest among Hispanic participants (78.8%, p<0.001).
In a large cohort receiving care across 3 diverse healthcare settings, cervical cancer screening and follow-up were below 80% coverage targets. Lower screening for Black patients was attenuated by controlling for insurance and site of care, underscoring the role of systemic inequity. In addition, it is crucial to improve follow-up after abnormalities are identified, which was low for all populations.
Near elimination of cervical cancer in the United States is possible in coming decades, yet inequities will delay this achievement for some populations. We sought to explore the effects of human ...papillomavirus (HPV) vaccination on disparities in cervical cancer incidence between high- and low-poverty U.S. counties.
We calibrated a dynamic simulation model of HPV infection to reflect average counties in the highest and lowest quartile of poverty (percent of population below federal poverty level), incorporating data on HPV prevalence, cervical cancer screening, and HPV vaccination. We projected cervical cancer incidence through 2070, estimated absolute and relative disparities in incident cervical cancer for high- versus low-poverty counties, and compared incidence with the near-elimination target (4 cases/100,000 women annually).
We estimated that, on average, low-poverty counties will achieve near-elimination targets 14 years earlier than high-poverty counties (2029 vs. 2043). Absolute disparities by county poverty will decrease, but relative differences are estimated to increase. We estimate 21,604 cumulative excess cervical cancer cases in high-poverty counties over the next 50 years. Increasing HPV vaccine coverage nationally to the Healthy People 2020 goal (80%) would reduce excess cancer cases, but not alter estimated time to reach the near-elimination threshold.
High-poverty U.S. counties will likely be delayed in achieving near-elimination targets for cervical cancer and as a result will experience thousands of potentially preventable cancers.
Alongside vaccination efforts, it is important to address the role of social determinants and health care access in driving persistent inequities by area poverty.
Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we ...demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus.
This paper explores the relationship between firms' strategies to share knowledge with their innovation system and innovative performance. The empirical analysis showed that many firms designed ...strategies to share technological knowledge with competitors, and those firms that shared knowledge with their innovation system earned higher innovative performance than firms that did not share knowledge. In addition, firms that interacted with their global innovation system earned higher innovative performance than firms that interacted with only their national innovation system. These results should help managers and researchers understand how to devise technology strategies in globally integrated industries.
Roux-en-Y gastric bypass (RYGB) surgery is the second most common weight loss surgery in the United States. Treatment of pancreaticobiliary disease in this patient population is challenging due to ...the altered anatomy, which limits the use of standard instruments and techniques. Both nonoperative and operative modalities are available to overcome these limitations, including device-assisted (DAE) endoscopic retrograde cholangiopancreatography (ERCP), laparoscopic-assisted (LA) ERCP, and endoscopic ultrasound-directed transgastric ERCP (EDGE). The aim of this study was to compare the cost-effectiveness of ERCP-based modalities for treatment of pancreaticobiliary diseases in post-RYGB patients.
A decision tree model with a 1-year time horizon was used to analyze the cost-effectiveness of EDGE, DAE-ERCP, and LA-ERCP in post-RYGB patients. Monte Carlo simulation was used to assess a plausible range of incremental cost-effectiveness ratios, net monetary benefit calculations, and a cost-effectiveness acceptability curve. One-way sensitivity analyses and probabilistic sensitivity analyses were also performed to assess how changes in key parameters affected model conclusions.
EDGE resulted in the lowest total costs and highest total quality-adjusted life-years (QALY) for a total of $5188/QALY, making it the dominant alternative compared with DAE-ERCP and LA-ERCP. In probabilistic analyses, EDGE was the most cost-effective modality compared with LA-ERCP and DAE-ERCP in 94.4 % and 97.1 % of simulations, respectively.
EDGE was the most cost-effective modality in post-RYGB anatomy for treatment of pancreaticobiliary diseases compared with DAE-ERCP and LA-ERCP. Sensitivity analysis demonstrated that this conclusion was robust to changes in important model parameters.
PDF
