The epidemiology of dermatofibrosarcoma protuberans incidence, metastasis, and death among various population groups: A Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Limited information exists regarding the epidemiology, metastasis, and survival of dermatofibrosarcoma protuberans (DFSP). OBJECTIVE: To measure DFSP incidence and assess metastasis and survival outcomes. METHODS: Incidence rate, overall and DFSP-specific survival outcomes for primary DFSP tumors contained in the Surveillance, Epidemiology, and End Results (SEER) registry were analyzed via quasi-Poisson regression, Cox, and competing risk analyses. RESULTS: DFSP incidence rate was 6.25 (95% CI, 5.93-6.57) cases per million person-years with significantly higher incidence observed among Black individuals than White individuals (8.74 vs 4.53). DFSP with larger tumor size (≥3 cm, odds ratio [OR]: 2.24; 95% CI, 1.62-3.12; P < .001) and tumors located on the head and neck (OR: 4.88; 95% CI, 3.31-7.18; P < .001), and genitalia (OR: 3.16; 95% CI, 1.17-8.52; P = .023) were associated with significantly increased risk of metastasis whereas higher socioeconomic status was associated with significantly decreased risk of metastasis. Larger tumor size (≥3 cm), regardless of location, and age (≥60 years) were associated with significantly worse overall and cancer-specific survival. LIMITATIONS: Retrospective design of SEER. CONCLUSION: DFSP incidence is 2-fold higher among Black than White individuals. The risk of DFSP metastasis is significantly increased with tumor size ≥3 cm and tumors located on head and neck, and genitalia. Larger tumor size (≥ 3 cm), regardless of location, and age (≥60 years) are the most important prognostic indicators of survival.

The Association between Alopecia and Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

IMPORTANCE: The link between autoimmune gut disorders and different types of hair loss conditions has been recently investigated with an increased interest. With acknowledgement of the connection between immune dysregulation and the gut microbiome, this pathway is now becoming recognized as playing an important role in hair growth. The inflammatory cascade that results from the disruption of gut integrity such as seen in inflammatory bowel diseases (IBD) has been associated with certain types of alopecia. OBJECTIVE: The aim of this work was to evaluate the association between alopecia and IBD. EVIDENCE REVIEW: A primary literature search was conducted using the PubMed, Embase, and Web of Science databases to identify articles on co-occurring alopecia and IBD from 1967 to 2020. A total of 79 studies were included in the review. A one-way proportional meta-analysis was performed on 19 of the studies to generate the pooled prevalence of alopecia and IBD. FINDING: The pooled prevalence of non-scarring alopecia among IBD patients was 1.12% (k = 7, I2 = 98.6%, 95% CI 3.1-39.9); the prevalence of IBD among scarring and non-scarring alopecia was 1.99% (k = 12; I2 = 99%, 95% CI 6.2-34). The prevalence of non-scarring alopecia areata (AA) among IBD was compared to the prevalence of AA in the general population (0.63 vs. 0.1%; p < 0.0001). Similarly, the prevalence of IBD among the scarring and non-scarring alopecia groups was compared to the prevalence of IBD in the general population (1.99 vs. 0.396%; p = 0.0004). CONCLUSION: IBD and alopecia, particularly AA, appear to be strongly associated. Dermatology patients with alopecia may benefit from screening for IBD.

Changes in Bone Mineral Density of the Femur and Tibia Before Injury to 2 Years After Anterior Cruciate Ligament Reconstruction in Division I Collegiate Athletes.

BACKGROUND: Osteoarthritis (OA) is a significant long term concern after anterior cruciate ligament (ACL) reconstruction (ACLR). A low bone mineral density (BMD), particularly in the subchondral region, has been associated with the development of OA and is evident at the knee in patients long after ACLR. It is unknown if persistent BMD deficits are present in high level collegiate athletes. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate bilateral changes in the BMD of the femur and tibia from before the injury to 24 months after ACLR in collegiate athletes. We hypothesized that the BMD of both the distal femur and the proximal tibia would be significantly reduced within the surgical limb initially postoperatively but return to preinjury levels by 24 months after ACLR. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 33 Division I collegiate athletes were identified between 2010 and 2021 (13 female) who underwent total body dual-energy X-ray absorptiometry (DXA) before sustaining an ACL injury. DXA was repeated at 6, 12, and 24 months after ACLR. Linear mixed effects models assessed differences in the BMD at 5%, 15%, and 50% of the femur's length (F5, F15, F50) and at 5%, 15%, and 50% of the tibia's length (T5, T15, T50) within each limb from before the injury to 24 months after ACLR, reported as Tukey-adjusted P values. RESULTS: Compared with before the injury, the BMD at F5 of the surgical limb was reduced by 0.15 g/cm2 (SE, 0.02 g/cm2) at 6 months (P < .001). The BMD at F15 of the surgical limb was reduced by 0.06 g/cm2 (SE, 0.01 g/cm2), 0.09 g/cm2 (SE, 0.01 g/cm2), and 0.09 g/cm2 (SE, 0.01 g/cm2) at 6, 12, and 24 months, respectively (all P < .001). The BMD at T5 of the nonsurgical limb was reduced by 0.07 g/cm2 (SE, 0.02 g/cm2) at 12 months (P = .02) and 0.10 g/cm2 (SE, 0.02 g/cm2) at 24 months (P = .001). The BMD at T15 of the surgical limb was reduced by 0.07 g/cm2 (SE, 0.01 g/cm2) at 6 months and 0.08 g/cm2 (SE, 0.02 g/cm2) at 12 months (P < .001). CONCLUSION: BMD deficits at F15 of the surgical limb persisted out to 24 months (-7.1%) after ACLR compared with before the injury in collegiate athletes. The BMD at F5 and T15 of the surgical limb was reduced at 6 and 12 months but not at 24 months compared with preinjury levels. For the nonsurgical limb, no significant differences were detected, except for the T5 region at 12 months (-5.1%) and 24 months (-7.2%). The BMD at F50 and T50 of both limbs was not significantly different than preinjury levels at any time after ACLR.

A Cell-Free Screen for Bacterial Membrane Disruptors Identifies Mefloquine as a Novel Antibiotic Adjuvant.

Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinderTM V.11 Collection and the Prestwick Chemical Drug Library®. The screen identified 35 "positives" (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine's activity against Staphylococcus aureus showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a ß-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant S. aureus. This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.

An in silico analysis of primary and secondary structure specificity determinants for human peptidylarginine deiminase types 2 and 4.

Human peptidylarginine deiminases (hPADs) are a family of five calcium-dependent enzymes that facilitate citrullination, which is the post-translational modification of peptidyl arginine to peptidyl citrulline. The isozymes hPAD2 and hPAD4 have been implicated in the development and progression of several autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. To better characterize the primary and secondary structure determinants of citrullination specificity, we mined the literature for protein sequences susceptible to citrullination by hPAD2 or hPAD4. First, protein secondary structure classification (α-helix, ß-sheet, or coil) was predicted using the PSIPRED software. Next, we used motif-x and pLogo to extract and visualize statistically significant motifs within each data set. Within the data sets of peptides predicted to lie in coil regions, both hPAD2 and hPAD4 appear to favor citrullination of glycine-containing motifs, while distinct hydrophobic motifs were identified for hPAD2 citrullination sites predicted to reside within α-helical and ß-sheet regions. Additionally, we identified potential substrate overlap between coil region citrullination and arginine methylation. Together, these results confirm the importance and offer some insight into the role of secondary structure elements for citrullination specificity, and provide biological context for the existing hPAD specificity and arginine post-translational modification literature.

Co-existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) results from the collaboration of multiple genetic abnormalities in the transformation of T-cell progenitors. Plant homeodomain finger protein 6 (PHF6) has recently been established as a key tumor suppressor, which is mutated in T-ALL; however, the clinical significance of PHF6 mutations has not been fully determined in adult T-ALL. In the present study, amplification of the PHF6 exons was performed, followed by DNA sequencing to identify the genomic mutations and examine the expression of PHF6 in adult patients with T-ALL. The correlation between PHF6 mutations and clinical features was also analyzed using a χ2 test, and between PHF6 mutations and survival curve using the Kaplan-Meier methods. PHF6 mutations were detected in 27.1% of the Chinese adults with T-ALL (16/59), 10 of which were found to be novel mutations. A significantly lower expression level of PHF6 was observed in T-ALL patients with PHF6 mutations compared with those without mutations. Of the observed mutations in PHF6, 6/16 were frame-shift mutations, indicating a PHF6 dysfunction in those patients. Of note, PHF6 mutations were found to be significantly associated with older age, lower hemoglobin levels, higher frequency of CD13 positivity and higher incidence of splenomegaly or lymphadenopathy. Furthermore, PHF6 mutations were found to be significantly correlated with Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) mutations. The patients with T-ALL with co-existence of the two mutations had a significantly shorter event-free survival and a poor prognosis. The present results indicated that PHF6 is inactivated in adult T-ALL, due to its low expression and mutations. The present data indicated the synergistic effect of PHF6 and NOTCH1 mutations, as well as their co-existence, on the oncogenesis of adult T-ALL, and their potential as a prognostic marker for the disease.

High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement.

Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.