School of Medicine

Smoking plays an underappreciated role in breast cancer progression, increasing recurrence and mortality in patients. Here, we show that S100A8/A9 innate immune signaling is a molecular mechanism that identifies smoking-related breast cancers and underlies their enhanced malignancy. In contrast to acute exposure, chronic nicotine increased tumorigenicity and reprogrammed breast cancer cells to express innate immune response genes. This required the α7 nicotinic acetylcholine receptor, which elicited dynamic changes in cell differentiation, proliferation, and expression of secreted cytokines, such as S100A8 and S100A9, as assessed by unbiased scRNA-seq. Indeed, pharmacologic or genetic inhibition of S100A8/A9-RAGE receptor signaling blocked nicotine's tumor-promoting effects. We also discovered Syntaphilin (SNPH) as an S100A8/A9-dependent gene enriched specifically in estrogen receptor-negative (ER^-) cancers from former smokers, linking this response to patient disease. Together, our findings describe a new α7 nAChR-S100A8/A9-Syntaphilin immune signaling module that drives nicotine-induced tumor progression and distinguishes smoking-related patient disease as a distinct subset of aggressive breast cancers.

Disparities persist throughout medicine, including among conference speakership invitations. The National Institutes of Health have highlighted the importance of diversity at academic conferences. We assessed the gender composition of speakers at the American Society for Apheresis (ASFA) annual meeting. We assessed all session chairs and speakers at the annual ASFA meeting from 2019 to 2024. Two authors independently assessed individuals genders. The primary outcome was the gender composition of all session chairs and speakers by position. Subset analyzes were performed to assess the gender composition of unique individuals (i.e., examining the total number of unique men and women, independent of the number of sessions at which they spoke) and by professional degree. 820 positions (665 speaker positions and 155 chair positions) were identified; women comprised significantly more positions than men [64.3%, 528/820 (95% CI 61.1%-67.6%) vs. 35.6% 292/820 (32.4%-38.9%); p < 0.0001]. 52.7% (432/820) of all session positions were held by physicians, with no significant difference in the gender composition [women 47.5%, 205/432 (42.8%-52.2%) vs. men 52.6%, 227/432 (47.8%-57.2%); p = 0.31]. When limited to unique physician individuals, women were significantly outnumbered by men [40.1%, 71/177 (33.2%-47.5%) vs. 59.9%, 106/177 (52.5%-66.8%); p = 0.01]. This analysis demonstrated mixed findings, with more women across all positions overall but significantly more men when limited to unique physicians. Diversity in conference positions begets a broader array of perspectives, knowledge, and expertise, and can aid in realizing greater diversity in related areas. Thus, academic conference diversity should be prioritized and thoughtfully pursued.

Background

Case presentation

Conclusion

Immune thrombotic thrombocytopenic purpura (iTTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular occlusion secondary to acquired ADAMTS13 deficiency. Contemporary data regarding iTTP treatment practices in the US, including the use of caplacizumab, are lacking. We aimed to characterize the demographics and therapies, including medications and apheresis practices, in patients with iTTP in the US. We retrospectively analyzed iTTP cases at 15 sites in the US that provide comprehensive care for patients with iTTP. The time-period assessed was from January 1, 2017 to December 31, 2021. Our primary objective was to analyze data by iTTP episode, inclusive of initial episodes and relapses. A total of 390 iTTP episodes were reported for 280 unique individuals (187 females, 93 males). Thirty-day mortality was 3.7% (14/374), and 6-month mortality was 7.4% (27/367). TPE details were reported for 343 episodes, among which 261 underwent at least one procedure (median 6, IQR 3-11). Among the 261 episodes with at least one therapeutic plasma exchange (TPE) performed, 82.0% (214/261) used only plasma. Caplacizumab was used either alone or in combination with other agents in 43 (11.0%) episodes. Management strategies for iTTP remain varied across centers in the US, with a variety of combinations for TPE replacement fluids and therapeutic agents, as well as limited use of caplacizumab. Further research and standardization of treatment regimens may further reduce mortality in this condition.

Understanding flavivirus immunity is critical for the development of pan-flavivirus vaccines. Dendritic cells (DC) coordinate antiviral innate and adaptive immune responses, and they can be targeted by flaviviruses as a mechanism of immune evasion. Using an unbiased genome-wide approach designed to specifically identify flavivirus-modulated pathways, we found that, while dengue virus (DENV) robustly activates DCs, Zika virus (ZIKV) causes minimal activation of genes involved in DC activation, maturation, and antigen presentation, reducing cytokine secretion and the stimulation of allogeneic and peptide-specific T cell responses. Mechanistically, ZIKV inhibits DC maturation by suppressing NF-κB p65 recruitment and the subsequent transcription of proinflammatory and DC maturation-related genes. Thus, we identify a divergence in the effects of ZIKV and DENV on the host T cell response, highlighting the need to factor such differences into the design of anti-flavivirus vaccines.

Pregnancys effects on the brain, behavior, and hormones provide a unique opportunity to study how the immune system integrates these adaptations and influences mental health.

Stenotrophomonas maltophilia is an understudied, gram-negative, aerobic bacterium that is widespread in the environment and increasingly a cause of opportunistic infections. Treating S. maltophilia remains difficult, leading to an increase in disease severity and higher hospitalization rates in people with cystic fibrosis, cancer, and other immunocompromised health conditions. The lack of effective antibiotics has led to renewed interest in phage therapy; however, there remains a great need for well-characterized phages, especially against S. maltophilia. In response to an oncology patient with a sepsis infection, we collected 18 phages from Southern California wastewater influent that exhibit different plaque morphology against S. maltophilia host strain B28B. We hypothesized that, when combined into a cocktail, genetically diverse phages would give rise to distinct lytic infection kinetics that would enhance bacterial killing when compared to the individual phages alone. We identified three genetically distinct clusters of phages, and a representative from each group was further investigated and screened for potential therapeutic use. The results demonstrated that the three-phage cocktail significantly suppressed bacterial growth compared with individual phages when observed for 48 h. We also assessed the lytic impacts of our three-phage cocktail against a collection of 46 S. maltophilia strains to determine if a multi-phage cocktail has an expanded host range. Our phages remained strain-specific and infected >50% of tested strains. In six clinically relevant S. maltophilia strains, the multi-phage cocktail has enhanced suppression of bacterial growth. These findings suggest that specialized phage cocktails may be an effective avenue of treatment for recalcitrant S. maltophilia infections resistant to current antibiotics.

BACKGROUND: Follicular variant papillary thyroid carcinoma is a distinct subtype of papillary thyroid carcinoma that can occasionally present with aggressive features, including distant metastases and extrathyroidal extension. While radioactive iodine ablation is a well-established treatment for residual disease, its post-treatment effects on tracheal and paratracheal structures remain poorly characterized. CASE PRESENTATION: A 22-year-old male individual of Taiwanese descent presented with an enlarged neck mass and was diagnosed with follicular variant papillary thyroid carcinoma. He underwent thyroidectomy, modified radical neck dissection, and postoperative radioactive iodine-131 ablation (100 mCi). A total of 1 year later, a chest computed tomography revealed a paratracheal soft tissue nodule and tracheal nodularity. Bronchoscopy with endobronchial ultrasound-guided sampling identified multiple 2-3 mm submucosal tracheal nodules containing white exudate. Cytopathologic analysis of both the paratracheal soft tissue nodule and the tracheal wall nodules revealed mucinous material without evidence of malignancy or inflammation. Microbiologic studies were negative for infection. CONCLUSION: These atypical bronchoscopic and pathologic findings likely represent post-radioactive iodine treatment changes. The patient remained without evidence of disease for 22 months, ongoing on thyroid suppression levels of thyroxine hormone replacement. The case represents successful radioactive iodine treatment of papillary thyroid carcinoma residual disease after surgical resection, with the first described pathologic findings to correlate with these post-treatment changes.

BACKGROUND: The creatine-creatine kinase-phosphocreatine (Cr-CK-PCr) system maintains intracellular ratios of ATP/ADP for support of cellular functions and has been characterized at the placental-uterine interface of rodents, primates, swine and sheep, and thus may support fetal development. This study determined effects of dietary supplementation of creatine (Cr) to gestating gilts on fetal development, the number and ratio of primary and secondary muscle fibers, and on protein expression in endometrium and fetal biceps-femoris muscle, respectively in fetal pigs on d 60 and d 90 of gestation. METHODS: Reproductively mature gilts were synchronized to estrus using Matrix, observed for estrus (d 0), and artificially inseminated 12 h and 36 h later. Gilts were individually housed and fed 0.86 kg of 14% crude protein diet twice daily that meets nutritional requirements for pregnant gilts. Gilts were assigned to either basal diet control (CON) group, or Cr supplemented group (provided 30 g Cr monohydrate daily) from d 10 to either d 60 or d 90 of gestation. Gilts were euthanized and hysterectomized on either d 60 or d 90 of gestation. These protocols were completed in two replicates, as gilts were bred in spring and euthanized in summer or bred in fall and euthanized in winter (n = 20 gilts/replicate). Litter size, crown-rump length, sex, and fetal weight was recorded. Three female and male fetuses closest to mean litter weight were selected to assess effects of treatment on weight of fetal brain, kidney, liver, spleen, and biceps-femoris muscle. Data were analyzed to determine effects of treatment, days of gestation, replicate, and sex on litter size, fetal measurements, and incidence of intrauterine growth restriction. RESULTS: Dietary Cr supplementation increased fetal brain weight to body weight ratios on d 90 of gestation (P < 0.05) and fetal kidney weight to body weight ratios on d 60 of gestation (P < 0.01), while days of gestation had significant effect on expression of mitochondrial CK isoform in gilt endometria (P < 0.05). CONCLUSIONS: Results suggest that dietary supplementation of Cr in gestating gilts enhanced development of select fetal organs and contribute to understanding roles of the Cr-CK-PCr system in pregnancy.

Precisely timed immune adaptations, observed in the maternal circulation, underpin the notion of an immune clock of human pregnancy that supports its successful progression and completion at delivery. This immune clock is divided into three immunological phases, with the first phase starting at the time of conception and implantation, shifting into the second phase that supports homeostasis and tolerance throughout pregnancy, and culminating in the last phase of labor and parturition. Disruptions of this immune clock are reported in pregnancy complications such as spontaneous preterm birth. However, our understanding of the immune clock preceding spontaneous preterm birth remains scattered. In this review, we describe the chronology of maternal immune cell adaptations during healthy pregnancies and highlight its disruption in spontaneous preterm birth. With a focus on single-cell cytometric, proteomic and transcriptomic approaches, we review recent studies of term and spontaneous preterm pregnancies and discuss the need for future prospective studies aimed at tracking pregnancies longitudinally on a multi-omic scale. Such studies will be critical in determining whether spontaneous preterm pregnancies progress at an accelerated pace or follow a preterm-intrinsic pattern when compared to those delivered at term.