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Plasmodium vivax is the predominant malaria parasite in Latin America. Its colonization history in the region is rich and complex, and is still highly debated, especially about its origin(s). Our study employed cutting-edge population genomic techniques to analyze whole genome variation from 620 P. vivax isolates, including 107 newly sequenced samples from West Africa, Middle East, and Latin America. This sampling represents nearly all potential source populations worldwide currently available. Analyses of the genetic structure, diversity, ancestry, coalescent-based inferences, including demographic scenario testing using Approximate Bayesian Computation, have revealed a more complex evolutionary history than previously envisioned. Indeed, our analyses suggest that the current American P. vivax populations predominantly stemmed from a now-extinct European lineage, with the potential contribution also from unsampled populations, most likely of West African origin. We also found evidence that P. vivax arrived in Latin America in multiple waves, initially during early European contact and later through post-colonial human migration waves in the late 19th-century. This study provides a fresh perspective on P. vivax's intricate evolutionary journey and brings insights into the possible contribution of West African P. vivax populations to the colonization history of Latin America.

Patients with human immunodeficiency virus (HIV) are at increased risk for developing other gynecologic conditions, including herpes simplex virus (HSV) and vulvar intraepithelial neoplasia (VIN)/carcinoma. We describe the case of a woman with a history of microinvasive vulvar squamous cell carcinoma who presented with hypertrophic ulcerated vulvar and peri-anal masses concerning for malignancy. This case highlights the need to maintain a high index of suspicion for malignancy and herpes simplex virus, even with negative polymerase chain reaction (PCR) test, as well as the difficulty of treating this often-resistant lesion.

Objectives: The prognosis of patients presenting with stage IVB uterine serous carcinoma (USC) remains extremely poor, with a reported 5-year survival of 1 cm. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: Final analysis included 68 patients. There was no difference in the frequency of treatment delays between regimens (p = 0.832). 96% of patients received platinum-based chemotherapy. There was no difference in the age (p = 0.227), race (p = 0.936), type of radiotherapy (p = 0.852) or chemotherapy regimen received (p = 0.996) between R1 and R2 cohorts. The median PFS for all patients was 8 months and the median OS was 13 months. Cytoreduction to R1 was associated with a median PFS of 9 months, compared to R2 with a median PFS of 4 months (p

Metastasis of non-mammary tumors to the breast are uncommon, representing

Chronic hepatitis D is one of the most severe and aggressive forms of chronic viral hepatitis with a high risk of developing hepatocellular carcinoma (HCC). It results from the co-infection of the liver with the hepatitis B virus (HBV) and its satellite, the hepatitis D virus (HDV). Although current therapies can control HBV infection, no treatment that efficiently eliminates HDV is available and novel therapeutic strategies are needed. Although the HDV cycle is well described, the lack of simple experimental models has restricted the study of host–virus interactions, even if they represent relevant therapeutic targets. In the last few years, the discovery of the sodium taurocholate co-transporting polypeptide (NTCP) as a key cellular entry factor for HBV and HDV has allowed the development of new cell culture models susceptible to HBV and HDV infection. In this review, we summarize the main in vitro model systems used for the study of HDV entry and infection, discuss their benefits and limitations and highlight perspectives for future developments.

T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance.

mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk.

Author(s): Laura C. Pinheiro [sup.1] [sup.2] [sup.3] , Orysya Soroka [sup.1] , Dominic T. Razon [sup.1] [sup.2] , Francesse Antoine [sup.1] [sup.2] , Julia Rothman [sup.4] , Margaux J. Kanis [...], Cancer fatalism-the belief that death is inevitable when cancer is present-has been identified as a barrier to cancer screening, detection, and treatment. Our study examined the relationship between self-reported cancer fatalism and adherence to cancer screening guidelines of the breasts, cervix, colon, and prostate among a diverse sample of urban-dwelling adults in Brooklyn, New York. Between May 2019 and August 2020, we conducted a cross-sectional survey of adults 40 + years of age (n = 2,341) residing in Brooklyn neighborhoods with high cancer mortality. Multivariable logistic regression models were used to assess the odds of reporting cancer screening completion across three fatalistic cancer belief categories (low, med, high). Participants' median age was 61 (IQR 51, 71) years, 61% were women, 49% self-identified as non-Hispanic black, 11% Hispanic, 4% Asian, and 6% more than one race. There were no statistically significant differences in the proportion of low, some, or high fatalistic beliefs identified among male respondents compared to women. Among women, we observed that high fatalistic cancer beliefs were associated with higher odds (OR 2.01; 95% CI 1.10-3.65) of completing breast but not cervical (1.04; CI 0.55-1.99) or colon (1.54; CI 0.88-2.69) cancer screening. Men with high fatalistic cancer beliefs had a trend towards lower odds of prostate screening (OR 0.53: 95% CI 0.18-1.57) compared to men with low fatalistic beliefs, but neither was statistically significant. Findings suggest that high fatalistic cancer beliefs may be an important factor in cancer screening utilization among women. Further examination in longitudinal cohorts with a larger sample of men may be needed in order to identify any significant effect.

Plasmodium vivax is the predominant malaria parasite in Latin America. Its colonization history in the region is rich and complex, and is still highly debated, especially about its origin(s). Our study employed cutting-edge population genomic techniques to analyze whole genome variation from 620 P. vivax isolates, including 107 newly sequenced samples from West Africa, Middle East, and Latin America. This sampling represents nearly all potential source populations worldwide currently available. Analyses of the genetic structure, diversity, ancestry, coalescent-based inferences, including demographic scenario testing using Approximate Bayesian Computation, have revealed a more complex evolutionary history than previously envisioned. Indeed, our analyses suggest that the current American P. vivax populations predominantly stemmed from a now-extinct European lineage, with the potential contribution also from unsampled populations, most likely of West African origin. We also found evidence that P. vivax arrived in Latin America in multiple waves, initially during early European contact and later through post-colonial human migration waves in the late 19th-century. This study provides a fresh perspective on P. vivax's intricate evolutionary journey and brings insights into the possible contribution of West African P. vivax populations to the colonization history of Latin America. Author summary: Our study investigates the origins and spread of Plasmodium vivax in Latin America, the primary malaria parasite in this region. By analyzing genetic data from 620 P. vivax samples worldwide, including new samples from West Africa, the Middle East, and Latin America, we were able to reconstruct the evolutionary history of the parasite in this region. Our findings indicate that the current P. vivax strains in Latin America mainly descended from a now-extinct European lineage. Additionally, we found evidence suggesting that several migration waves following human migrations waves may have contributed to the parasite diversity, with possible contributions from West African populations during the transatlantic slave trade (16th to 19th century) and further input from Europe during post-colonial human migrations in the late 19th century. This study offers a fresh perspective on how historical human migrations have shaped the genetic landscape of P. vivax in Latin America. These insights are valuable for understanding the parasite evolution and may help inform strategies for malaria control and prevention in the future. [ABSTRACT FROM AUTHOR]

Application of hydrostatic pressure shifts protein conformational equilibria in a direction to reduce the volume of the system. A current view is that the volume reduction is dominated by elimination of voids or cavities in the protein interior via cavity hydration, although an alternative mechanism wherein cavities are filled with protein side chains resulting from a structure relaxation has been suggested [López CJ, Yang Z, Altenbach C, Hubbell WL (2013) Proc Natl Acad Sci USA 110(46):E4306-E4315]. In the present study, mechanisms for elimination of cavities under high pressure are investigated in the L99A cavity mutant of T4 lysozyme and derivatives thereof using site-directed spin labeling, pressure-resolved double electron-electron resonance, and high-pressure circular dichroism spectroscopy. In the L99A mutant, the ground state is in equilibrium with an excited state of only ∼ 3% of the population in which the cavity is filled by a protein side chain [Bouvignies et al. (2011) Nature 477(7362):111-114]. The results of the present study show that in L99A the native ground state is the dominant conformation to pressures of 3 kbar, with cavity hydration apparently taking place in the range of 2-3 kbar. However, in the presence of additional mutations that lower the free energy of the excited state, pressure strongly populates the excited state, thereby eliminating the cavity with a native side chain rather than solvent. Thus, both cavity hydration and structure relaxation are mechanisms for cavity elimination under pressure, and which is dominant is determined by details of the energy landscape.

T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance.

In migratory animals, high mobility may reduce population structure through increased dispersal and enable adaptive responses to environmental change, whereas rigid migratory routines predict low dispersal, increased structure, and limited flexibility to respond to change. We explore the global population structure and phylogeographic history of the bar‐tailed godwit, Limosa lapponica, a migratory shorebird known for making the longest non‐stop flights of any landbird. Using nextRAD sequencing of 14,318 single‐nucleotide polymorphisms and scenario‐testing in an Approximate Bayesian Computation framework, we infer that bar‐tailed godwits existed in two main lineages at the last glacial maximum, when much of their present‐day breeding range persisted in a vast, unglaciated Siberian‐Beringian refugium, followed by admixture of these lineages in the eastern Palearctic. Subsequently, population structure developed at both longitudinal extremes: in the east, a genetic cline exists across latitude in the Alaska breeding range of subspecies L. l. baueri; in the west, one lineage diversified into three extant subspecies L. l. lapponica, taymyrensis, and yamalensis, the former two of which migrate through previously glaciated western Europe. In the global range of this long‐distance migrant, we found evidence of both (1) fidelity to rigid behavioural routines promoting fine‐scale geographic population structure (in the east) and (2) flexibility to colonise recently available migratory flyways and non‐breeding areas (in the west). Our results suggest that cultural traditions in highly mobile vertebrates can override the expected effects of high dispersal ability on population structure, and provide insights for the evolution and flexibility of some of the world's longest migrations. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite consensus recommendations, national genetic counseling and testing rates for gynecological cancers remain relatively low. Prior studies have also shown that referrals are fewer for people of minority backgrounds. This initial study aimed to determine what genetic counseling and testing rates are found in a diverse patient setting. High rates of genetic counseling and testing are demonstrated, with no racial disparities. Both endometrial and ovarian cancer data are presented simultaneously in a single study in the first of its kind, helping provide a broader combined perspective. Point-of-care genetic counseling and testing by gynecologic oncologists is a strategy that can be similarly adopted at other institutions to potentially reduce disparities. Further studies can identify other factors responsible for the successful counseling and testing rates and how they can be used to broaden the reach of these services at other centers with similar diverse populations. We investigated genetic counseling and testing rates for patients with gynecologic malignancy at a tertiary care center with a large minority population. Our retrospective cohort included newly diagnosed epithelial ovarian, fallopian tube, peritoneal, or endometrial cancer patients between January 2014 and June 2022. For endometrial cancer, 373 patients were identified. A total of 207 (55%) patients were screened using mismatch repair immunohistochemistry (MMR IHC). A total of 82 (40%) had MMR deficiencies on IHC. Of these, 63 (77%) received genetic counseling. A total of 62 (98%) underwent genetic testing, and ultimately, 7 (11%) were diagnosed with Lynch syndrome (LS). The overall rate of LS was 1.9%. MMR IHC testing increased steadily, reaching 100% in 2022. For ovarian cancer, 144 patients were identified. A total of 104 (72%) patients received genetic counseling, and 99 (95%) underwent genetic testing. Rates were not influenced by race, ethnicity, insurance type, or family history of cancer. They were significantly different by cancer stage (p < 0.01). The proportion of patients who received genetic counseling increased from 47% in 2015 to 100% in 2022 (p < 0.01). Most counseling was performed by a gynecologic oncologist (93%) as opposed to a genetic counselor (6.7%). Overall, 12 (8.3%) patients were BRCA+. High rates of counseling and testing were observed with few disparities. [ABSTRACT FROM AUTHOR]