Extending upon our previous publication Drummond, M. ; J. Chem. Inf. Model. 2019, 59, 1634−1644 , two additional computational methods are presented to model PROTAC-mediated ternary complex ...structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.
African American and Hispanic women are more likely to be diagnosed with aggressive forms of breast cancer. Disparities within each subtype of breast cancer have not been well documented.
Using data ...from 18 SEER cancer registries, we identified 102,064 women aged 20 years or older, diagnosed with invasive breast cancer in 2010-2011, and with known stage, hormone receptor (HR), and HER2 status. Associations between race/ethnicity and cancer stage and receipt of guideline-concordant treatment were evaluated according to HR/HER2 status.
Overall, African American and Hispanic women were 30% to 60% more likely to be diagnosed with stage II-IV breast cancer compared with non-Hispanic whites. African American women had 40% to 70% higher risks of stage IV breast cancer across all four subtypes. American Indian/Alaska Native women had a 3.9-fold higher risk of stage IV triple-negative breast cancer. African American and Hispanic whites were 30% to 40% more likely to receive non-guideline-concordant treatment for breast cancer overall and across subtypes.
Women in several racial/ethnic groups are more likely to be diagnosed with more advanced stage breast cancer. African American and American Indian/Alaska Native women in particular had the highest risk of being diagnosed with stage IV triple-negative breast cancer. African American and Hispanic women were also consistently at higher risk of not receiving guideline-concordant treatment across subtypes.
These findings provide important characterization of which subtypes of breast cancer racial/ethnic disparities in stage and treatment persist.
In 2010, Surveillance, Epidemiology, and End Results (SEER) registries began collecting human epidermal growth factor 2 (HER2) receptor status for breast cancer cases.
Breast cancer subtypes defined ...by joint hormone receptor (HR; estrogen receptor ER and progesterone receptor PR) and HER2 status were assessed across the 28% of the US population that is covered by SEER registries. Age-specific incidence rates by subtype were calculated for non-Hispanic (NH) white, NH black, NH Asian Pacific Islander (API), and Hispanic women. Joint HR/HER2 status distributions by age, race/ethnicity, county-level poverty, registry, stage, Bloom-Richardson grade, tumor size, and nodal status were evaluated using multivariable adjusted polytomous logistic regression. All statistical tests were two-sided.
Among case patients with known HR/HER2 status, 36810 (72.7%) were found to be HR(+)/HER2(-), 6193 (12.2%) were triple-negative (HR(-)/HER2(-)), 5240 (10.3%) were HR(+)/HER2(+), and 2328 (4.6%) were HR(-)/HER2(+); 6912 (12%) had unknown HR/HER2 status. NH white women had the highest incidence rate of the HR(+)/HER2(-) subtype, and NH black women had the highest rate of the triple-negative subtype. Compared with women with the HR(+)/HER2(-) subtype, triple-negative patients were more likely to be NH black and Hispanic; HR(+)/HER2(+) patients were more likely to be NH API; and HR(-)/HER2(+) patients were more likely to be NH black, NH API, and Hispanic. Patients with triple-negative, HR(+)/HER2(+), and HR(-)/HER2(+) breast cancer were 10% to 30% less likely to be diagnosed at older ages compared with HR(+)/HER2(-) patients and 6.4-fold to 20.0-fold more likely to present with high-grade disease.
In the future, SEER data can be used to monitor clinical outcomes in women diagnosed with different molecular subtypes of breast cancer for a large portion (approximately 28%) of the US population.
Several new therapeutic drugs are now available for the management of rheumatoid arthritis (RA). Given that RA has been associated with an increased risk of certain cancers like lymphoma and lung ...cancer, concern remains about the safety of (newer) immunosuppressants used in RA management as it relates to the risk of cancer.
Most meta-analyses of randomized clinical trials of tumor necrosis factor inhibitors (TNFi) have not observed an association between TNFi and risk of incident cancer. Studies of non-TNFi biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs and cancer are also reassuring but limited and of short-term follow-up. Regarding the use of DMARDs in patients with RA and a prior malignancy, retrospective studies have shown that TNFi use is not associated with recurrence.
There is a need for ongoing studies on the safety of non-TNFi bDMARDs and targeted synthetic disease modifying anti-rheumatic drugs and recurrent cancer. Further research is also needed to guide the patients, rheumatologists, and oncologists regarding the safest DMARDs to choose for patients with RA and a recent diagnosis of cancer.
The ability to control nanostructure shape and dimensions presents opportunities to design materials in which their macroscopic properties are dependent upon the nature of the nanoparticle. Although ...particle morphology has been recognized as a crucial parameter, the exploitation of the potential shape-dependent properties has, to date, been limited. Herein, we demonstrate that nanoparticle shape is a critical consideration in the determination of nanocomposite hydrogel properties. Using translationally relevant calcium-alginate hydrogels, we show that the use of poly(L-lactide)-based nanoparticles with platelet morphology as an adhesive results in a significant enhancement of adhesion over nanoparticle glues comprised of spherical or cylindrical micelles. Furthermore, gel nanocomposites containing platelets showed an enhanced resistance to breaking under strain compared to their spherical and cylindrical counterparts. This study opens the doors to a change in direction in the field of gel nanocomposites, where nanoparticle shape plays an important role in tuning mechanical properties.
Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation in various cellular processes including cell proliferation and differentiation, but the APA heterogeneity ...among single cells remains largely unknown. Single-cell RNA sequencing (scRNA-seq) has been extensively used to define cell subpopulations at the transcription level. Yet, most scRNA-seq data have not been analyzed in an "APA-aware" manner. Here, we introduce dynamic analysis of APA from single-cell RNA-seq (scDaPars), a bioinformatics algorithm to accurately quantify APA events at both single-cell and single-gene resolution using either 3'-end (10x Chromium) or full-length (Smart-seq2) scRNA-seq data. Validations in both real and simulated data indicate that scDaPars can robustly recover missing APA events caused by the low amounts of mRNA sequenced in single cells. When applied to cancer and human endoderm differentiation data, scDaPars not only revealed cell-type-specific APA regulation but also identified cell subpopulations that are otherwise invisible to conventional gene expression analysis. Thus, scDaPars will enable us to understand cellular heterogeneity at the post-transcriptional APA level.
Abstract
BACKGROUND:
Improved understanding of rod fracture (RF) in adult spinal deformity could be valuable for implant design, surgical planning, and patient counseling.
OBJECTIVE:
To evaluate ...symptomatic RF after posterior instrumented fusion for adult spinal deformity.
METHODS:
A multicenter, retrospective review of RF in adult spinal deformity was performed. Inclusion criteria were spinal deformity, age older than 18 years, and more than 5 levels posterior instrumented fusion. Rod failures were divided into early (⩽12 months) and late (>12 months).
RESULTS:
Of 442 patients, 6.8% had symptomatic RF. RF rates were 8.6% for titanium alloy, 7.4% for stainless steel, and 2.7% for cobalt chromium. RF incidence after pedicle subtraction osteotomy (PSO) was 15.8%. Among patients with a PSO and RF, 89% had RF at or adjacent to the PSO. Mean time to early RF (63%) was 6.4 months (range, 2-12 months). Mean time to late RF (37%) was 31.8 months (range, 14-73 months). The majority of RFs after PSO (71%) were early (mean, 10 months). Among RF cases, mean sagittal vertical axis improved from preoperative (163 mm) to postoperative (76.9 mm) measures (P < .001); however, 16 had postoperative malalignment (sagittal vertical axis >50 mm; mean, 109 mm).
CONCLUSION:
Symptomatic RF occurred in 6.8% of adult spinal deformity cases and in 15.8% of PSO patients. The rate of RF was lower with cobalt chromium than with titanium alloy or stainless steel. Early failure was most common after PSO and favored the PSO site, suggesting that RF may be caused by stress at the PSO site. Postoperative sagittal malalignment may increase the risk of RF.
The Net Reclassification Index (NRI) and its P value are used to make conclusions about improvements in prediction performance gained by adding a set of biomarkers to an existing risk prediction ...model. Although proposed only 5 years ago, the NRI has gained enormous traction in the risk prediction literature. Concerns have recently been raised about the statistical validity of the NRI.
Using a population dataset of 10000 individuals with an event rate of 10.2%, in which four biomarkers have no predictive ability, we repeatedly simulated studies and calculated the chance that the NRI statistic provides a positive statistically significant result. Subjects for training data (n = 420) and test data (n = 420 or 840) were randomly selected from the population, and corresponding NRI statistics and P values were calculated. For comparison, the change in the area under the receiver operating characteristic curve and likelihood ratio statistics were calculated.
We found that rates of false-positive conclusions based on the NRI statistic were unacceptably high, being 63.0% in the training datasets and 18.8% to 34.4% in the test datasets. False-positive conclusions were rare when using the change in the area under the curve and occurred at the expected rate of approximately 5.0% with the likelihood ratio statistic.
Conclusions about biomarker performance that are based primarily on a statistically significant NRI statistic should be treated with skepticism. Use of NRI P values in scientific reporting should be halted.
Disparities in breast cancer stage and mortality by race/ethnicity in the United States are persistent and well known. However, few studies have assessed differences across racial/ethnic subgroups of ...women broadly defined as Hispanic, Asian, or Pacific Islander, particularly using more recent data. Using data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) program, we evaluated the relationships between race/ethnicity and breast cancer stage, hormone receptor status, treatment, and mortality. The cohort consisted of 229,594 women 40–79 years of age diagnosed with invasive breast carcinoma between January 2000 and December 2006, including 176,094 non-Hispanic whites, 20,486 Blacks, 15,835 Hispanic whites, 14,951 Asians, 1,224 Pacific Islanders, and 1,004 American Indians/Alaska Natives. With respect to statistically significant findings, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women had 1.3–7.1-fold higher odds of presenting with stage IV breast cancer compared to non-Hispanic white women. Almost all groups were more likely to be diagnosed with estrogen receptor-negative/progesterone receptor-negative (ER−/PR−) disease with Black and Puerto Rican women having the highest odds ratios (2.4 and 1.9-fold increases, respectively) compared to non-Hispanic whites. Lastly, Black, Hawaiian, Puerto Rican, and Samoan patients had 1.5–1.8-fold elevated risks of breast cancer-specific mortality. Breast cancer disparities persist by race/ethnicity, though there is substantial variation within subgroups of women broadly defined as Hispanic or Asian. Targeted, multi-pronged interventions that are culturally appropriate may be important means of reducing the magnitudes of these disparities.
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