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Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-β)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-β/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-β/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-β/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-β pathway, Notch pathway, and TGF-β/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-β/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-β/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-β/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this era of precision medicine, incorporating quantitative measures of estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 expressions and genomic assays could more precisely identify neoadjuvant systemic therapy with the highest likelihood of response and tumor downstaging. In our recent study, we quantified the likelihood of achieving breast-conserving surgery (BCS vs. mastectomy) after neoadjuvant chemotherapy or endocrine therapy as a function of demographics, quantitative ER/PR/Ki-67 expressions, 21-gene recurrence scores, or 70-gene risk scores in early-stage, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Using the 2010-2020 National Cancer Database, we found that the BCS rate after neoadjuvant chemotherapy was higher among patients with high 21-gene recurrence scores, lower ER/PR expression, or higher Ki-67 expression. Most patients who received neoadjuvant endocrine therapy underwent BCS, which was mostly dependent on ER expression. Asian women were less likely than white women to undergo BCS after neoadjuvant treatments. Lack of health insurance was associated with lower odds of BCS in both neoadjuvant settings. Although our study provides insight into the associations of BCS with quantitative biomarkers at a single time point, several questions remain unanswered. With the evolving landscape of neoadjuvant therapies in development for HR-positive/HER2-negative breast cancer, ongoing work using quantitative biomarkers and genomic assay scores is needed to select the right neoadjuvant systemic therapy for the right patient. Given the increasing amount of data available at the time of breast cancer diagnosis, novel computational approaches are needed to integrate patient demographic and tumor-specific factors to predict the optimal treatment strategy and likelihood of BCS., (© 2024. Society of Surgical Oncology.)

Background: Given increased neoadjuvant therapy use in early-stage, hormone receptor (HR)-positive/HER2-negative breast cancer, we sought to quantify likelihood of breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) or endocrine therapy (NET) as a function of ER%/PR%/Ki-67%, 21-gene recurrence scores (RS), or 70-gene risk groups., Methods: We analyzed the 2010-2020 National Cancer Database. Surgery was categorized as "mastectomy/BCS." Logistic regression was performed. Adjusted odds ratios (AOR) were per 10-unit increase in ER%/PR%/Ki-67%., Results: Overall, 42.3% underwent BCS after NACT, whereas 64.0% did after NET. Increasing ER% (AOR = 0.96, 95% confidence interval [CI] 0.94-0.97) or PR% (AOR=0.98, 95% CI 0.96-0.99) was associated with lower odds of BCS after NACT. Increasing Ki-67% was associated with greater odds of BCS (AOR = 1.07, 95% CI 1.04-1.10). Breast-conserving surgery rates increased by ~20 percentage points, with Ki-67% ≥15 or RS >20. Patients with a low (43.0%, AOR = 0.50, 95% CI 0.29-0.88) or intermediate (46.4%, AOR = 0.58, 95% CI 0.41-0.81) RS were less likely than patients with a high RS (65.0%) to undergo BCS after NACT. Increasing ER% was associated with higher odds of BCS after NET (AOR = 1.09, 95% CI 1.01-1.17). Breast-conserving surgery rates increased by ~20 percentage points between ER <50% and >80%. In both cohorts, the odds of BCS were similar between 70-gene low-risk and high-risk groups. Asian or uninsured patients had lower odds of BCS., Conclusions: Neoadjuvant chemotherapy is unlikely to downstage tumors with a low-intermediate RS, higher ER%/PR%, or lower Ki-67%. Breast-conserving surgery after NET was most dependent on ER%. Findings could facilitate treatment decision-making based on tumor biology and racial/socioeconomic disparities and improve patient counseling on the likelihood of successful BCS., (© 2024. The Author(s).)

Saccharomyces cerevisiae, the primary microorganism involved in ethanol production, is hindered by the accumulation of ethanol, leading to reduced ethanol production. In this study, we employed histidine-modified Fe 3 O 4 nanoparticles (His-Fe 3 O 4 ) for the first time, to the best of our knowledge, as a method to enhance ethanol yield during the S. cerevisiae fermentation process. The results demonstrated that exposing S. cerevisiae cells to Fe 3 O 4 nanoparticles (Fe 3 O 4 NPs) led to increased cell proliferation and glucose consumption. Moreover, the introduction of His-Fe 3 O 4 significantly boosted ethanol content by 17.3% (p < 0.05) during fermentation. Subsequent findings indicated that the increase in ethanol content was associated with enhanced ethanol tolerance and improved electron transport efficiency. This study provided evidence for the positive effects of His-Fe 3 O 4 on S. cerevisiae cells and proposed a straightforward approach to enhance ethanol production in S. cerevisiae fermentation. The mediation of improved ethanol tolerance offers significant potential in the fermentation and bioenergy sectors., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Prostate cancer (PCa) is the second most common cancer and the fifth leading cause of cancer-related death among men. A comprehensive understanding of PCa progression is crucial for the development of innovative therapeutic strategies for its treatment. While WDR1 (WD-repeat domain 1) serves as a significant cofactor of actin-depolymerizing factor/cofilin, its role in PCa progression remains unknown. In this study, we demonstrated that knockdown of WDR1 in various PCa cells substantially inhibited cell proliferation, migration, and invasion in vitro, as confirmed at both the cellular and molecular levels. Moreover, the overexpression of WDR1 promoted PCa cell proliferation and metastasis in vitro. Mechanistically, we showed that the application of lithium chloride, an activator of the Wnt/β-Catenin signaling pathway, restored the suppressive effects of WDR1 deficiency on cell proliferation and migration in PCa cells. Our findings suggest that the WDR1-β-Catenin axis functions as an activator of the malignant phenotype and represents a promising therapeutic target for PCa treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the production of blood cells for clinical application. In two decades, almost all types of blood cells can be successfully generated from hPSCs through various differentiated strategies. Meanwhile, with a deeper understanding of hematopoiesis, higher efficiency of generating progenitors and precursors of blood cells from hPSCs is achieved. However, how to generate large-scale mature functional cells from hPSCs for clinical use is still difficult. In this review, we summarized recent approaches that generated both hematopoietic stem cells and mature lineage cells from hPSCs, and remarked their efficiency and mechanisms in producing mature functional cells. We also discussed the major challenges in hPSC-derived products of blood cells and provided some potential solutions. Our review summarized efficient, simple, and defined methodologies for developing good manufacturing practice standards for hPSC-derived blood cells, which will facilitate the translation of these products into the clinic., (© 2023. Chinese Society for Cell Biology.)

To explore the feasibility of an automatic machine-learning algorithm-based quality control system for the practice of diagnostic radiography, performance of a convolutional neural networks (CNN)-based algorithm for identifying radiographic (X-ray) views at different levels was examined with a retrospective, HIPAA-compliant, and IRB-approved study performed on 15,046 radiographic images acquired between 2013 and 2018 from nine clinical sites affiliated with our institution. Images were labeled according to four classification levels: level 1 (anatomy level, 25 classes), level 2 (laterality level, 41 classes), level 3 (projection level, 108 classes), and level 4 (detailed level, 143 classes). An Inception V3 model pre-trained with ImageNet dataset was trained with transfer learning to classify the image at all levels. Sensitivity and positive predictive value were reported for each class, and overall accuracy was reported for each level. Accuracy was also reported when we allowed for "reasonable errors". The overall accuracy was 0.96, 0.93, 0.90, and 0.86 at levels 1, 2, 3, and 4, respectively. Overall accuracy increased to 0.99, 0.97, 0.94, and 0.88 when "reasonable errors" were allowed. Machine learning algorithms resulted in reasonable model performance for identifying radiographic views with acceptable accuracy when "reasonable errors" were allowed. Our findings demonstrate the feasibility of building a quality-control program based on machine-learning algorithms to identify radiographic views with acceptable accuracy at lower levels, which could be applied in a clinical setting.

Low-dose computed tomography (CT) lung cancer screening is recommended by the US Preventive Services Task Force for high lung cancer-risk populations. In this study, we investigated an important factor affecting the CT dose-the scan length, for this CT exam. A neural network model based on the "UNET" framework was established to segment the lung region in the CT scout images. It was trained initially with 247 chest X-ray images and then with 40 CT scout images. The mean Intersection over Union (IOU) and Dice coefficient were reported to be 0.954 and 0.976, respectively. Lung scan boundaries were determined from this segmentation and compared with the boundaries marked by an expert for 150 validation images, resulting an average 4.7% difference. Seven hundred seventy CT low-dose lung screening exams were retrospectively analyzed with the validated model. The average "desired" scan length was 252 mm with a standard deviation of 28 mm. The average "over-range" was 58.5 mm or 24%. The upper boundary (superior) on average had an "over-range" of 17 mm, and the lower boundary (inferior) on average had an "over-range" of 41 mm. Further analysis of this data showed that the extent of "over-range" was independent of acquisition date, acquisition time, acquisition station, and patient age, but dependent on technologist and patient weight. We concluded that this machine learning method could effectively support quality control on the scan length for CT low-dose screening scans, enabling the eliminations of unnecessary patient dose.

A broadband metamaterial absorber (MA) composed of hexagonal-arranged single-sized titanium nitride (TiN) nano-disk array and monolayer molybdenum disulfide (MoS 2 ) is studied using finite-difference time-domain (FDTD) simulations. The structure of TiN nano-disk array/dielectric silica (SiO 2 )/aluminum (Al) is adopted in our design. By optimizing the dimension parameters of the structure, an average absorption of 96.1% is achieved from 400 to 850 nm. In addition, by inserting a monolayer MoS 2 which has high absorption at the short wavelength side underneath the TiN nano-disk array, an average absorption of 98.1% over the entire visible regime from 400 to 850 nm was achieved, with a peak absorption near 100% and absorption over 99% from 475 to 772 nm. Moreover, the absorber presented in this paper is polarization insensitive. This compact and unique design with TiN nano-disk/monolayer MoS 2 / SiO 2 /Al structure may have great potential for applications in photovoltaics and light trapping.

Background: The effectiveness of postmastectomy radiotherapy (PMRT) in terms of survival for breast cancer patients with American Joint Committee on Cancer (AJCC) pT1-2 and one to three tumor positive lymph nodes is controversial, especially in this era of more effective systemic treatment., Methods: Using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program between 1998 and 2008, this study respectively identified 93,793 and 36,299 women with AJCC pT1-2pN1 breast cancer who underwent mastectomy. The association of PMRT use with overall and cause-specific survival was examined using multivariable Cox models in subgroups defined by tumor stage., Results: In the NCDB cohort, 21.5 % of the patients (n = 20,236) received PMRT, and a very similar percentage (21.9 %, n = 7939) received PMRT in the SEER cohort. In the NCDB cohort, PMRT was associated with a 14 % relative risk reduction in all-cause mortality among the patients with two positive lymph nodes and tumors 2-5 cm in size or three positive nodes [hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.81-0.91; p < 0.0001], but PMRT had no beneficial effect for the patients with one positive node or two positive nodes and tumors 2 cm in size or smaller. Analysis of the SEER cohort confirmed this heterogeneous effect, showing PMRT to be associated with a 14 % relative risk reduction in breast cancer cause-specific mortality among the patients with two positive nodes and tumors 2-5 cm in size or three positive nodes (HR 0.86; 95 % CI 0.77-0.96; p = 0.007) but not in the other subgroup., Conclusion: The effectiveness of radiotherapy depends on the combination comprising the number of positive lymph nodes and tumor size, which may enable more precise patient selection for PMRT.

Key Message: Maize kernel row number might be dominated by a set of large additive or partially dominant loci and several small dominant loci and can be accurately predicted by fewer than 300 top KRN-associated SNPs. Kernel row number (KRN) is an important yield component in maize and directly affects grain yield. In this study, we combined linkage and association mapping to uncover the genetic architecture of maize KRN and to evaluate the phenotypic predictability using these detected loci. A genome-wide association study revealed 31 associated single nucleotide polymorphisms (SNPs) representing 17 genomic loci with an effect in at least one of five individual environments and the best linear unbiased prediction (BLUP) over all environments. Linkage mapping in three F2:3 populations identified 33 KRN quantitative trait loci (QTLs) representing 21 QTLs common to several population/environments. The majority of these common QTLs that displayed a large effect were additive or partially dominant. We found 70% KRN-associated genomic loci were mapped in KRN QTLs identified in this study, KRN-associated SNP hotspots detected in NAM population and/or previous identified KRN QTL hotspots. Furthermore, the KRN of inbred lines and hybrids could be predicted by the additive effect of the SNPs, which was estimated using inbred lines as a training set. The prediction accuracy using the top KRN-associated tag SNPs was obviously higher than that of the randomly selected SNPs, and approximately 300 top KRN-associated tag SNPs were sufficient for predicting the KRN of the inbred lines and hybrids. The results suggest that the KRN-associated loci and QTLs that were detected in this study show great potential for improving the KRN with genomic selection in maize breeding.

Background: Data on recent trends and correlates of utilization for accelerated partial breast irradiation using brachytherapy (APBI-b) for ductal carcinoma in situ (DCIS) are lacking., Methods: This study included 113,841 DCIS patients from the National Cancer Data Base, of whom 8,709 (6.5 %) underwent APBI-b and 105,132 (93.5 %) underwent external beam irradiation after lumpectomy between 2003 and 2011. Trends in APBI-b use, American Society for Radiation Oncology (ASTRO) guideline concordance, and independent factors related to APBI-b use were examined., Results: APBI-b use increased from 1.6 % in 2003 to 11.9 % in 2008 and then decreased to 9.1 % in 2011 (p < 0.001). Before 2009, 24.6 % of patients undergoing APBI-b were in the ASTRO guideline 'unsuitable' category, but this proportion decreased to 14.6 % after 2009 (p < 0.001). When adjusting for year of diagnosis, patient, tumor, and facility factors, the four strongest independent factors for APBI-b use were year of diagnosis followed by facility location, facility volume, and facility type. APBI-b use was highest in the East South Central census region (13.1 %) and lowest in the New England region (2.0 %). A statistically significant interaction was identified between facility type and volume. Patients in community cancer programs of large volume were more likely to receive APBI-b, whereas patients in larger academic programs were less likely to receive APBI-b., Conclusion: APBI-b for DCIS decreased from 2008 to 2011. After year of diagnosis, facility factors were most strongly associated with APBI-b use as opposed to patient and tumor factors. Reasons for these trends are multifactorial and deserve further study.

Background: Randomized trials have not demonstrated a survival benefit for axillary dissection in the elderly, but the use of axillary staging for women 70 years of age and older remains controversial., Methods: We utilized the National Cancer Data Base to study the use of axillary staging from 2004 to 2010 on 102,026 clinically node-negative and estrogen receptor-positive cases of pT1N0 tumors. Chi-square and logistic regression models were used to determine the trends and factors related to axillary staging., Results: Axillary nodes were examined in 88.9 % of the total cohort, and the trend significantly increased from 87.7 % in 2004 to 89.2 % in 2010. A total of 77.2 % of patients underwent lumpectomy and 22.8 % mastectomy, with 87.0 % of lumpectomy patients undergoing axillary staging compared to 95.5 % of mastectomy patients. Predictors of axillary staging examined were age, comorbidity, income, histology, grade, facility type, facility location, and population density. The strongest independent predictor of axillary staging was age: 96.0 % of women aged 70-75 years underwent axillary staging, versus 92.3 % of women 75-80 years old, 83.2 % of women 80-85 years old, 66.5 % of women 86-90 years old, and 45.6 % of women >90 years old. Patients treated at academic/research facilities were 18.5 % less likely (odds ratio 0.81, 95 % confidence interval 0.76-0.87) than community cancer programs to undergo axillary staging. There was significant regional variation among U.S. Census regions: patients treated in the Midwest were 3.8 times more likely to undergo axillary staging than those treated in the Northeast., Conclusions: Despite data indicating decreased utility, axillary staging remains overutilized in women with advancing age.

Background: Previous studies have demonstrated an increase in the utilization of accelerated partial-breast irradiation via brachytherapy (APBI-b), but larger, more contemporary studies examining overall APBI use are lacking., Methods: A total of 575,438 nonneoadjuvant American Joint Committee on Cancer stage 0 to II breast conservation patients were selected from the National Cancer Data Base from 2003 to 2010 who underwent either whole-breast irradiation or APBI., Results: Overall, 59,396 patients (10.3 %) underwent APBI. The use of APBI for the entire cohort increased from 3.4 % in 2003 to 12.8 % (p < 0.001) in 2008 and then decreased to 12.4 % in 2010. Three-dimensional conformal radiation increased from 0.8 to 2.2 %, intensity-modulated radiotherapy increased from 0.7 to 1.3 %, and brachytherapy (APBI-b) increased from 2.0 to 8.9 %. The most significant factors associated with APBI use were patient age and facility location. Patients 80-89 years old were 3.8 times more likely to undergo APBI compared to patients 30-39 years old (odds ratio [OR] 3.77, 95 % confidence interval [CI] 3.45-4.10, p < 0.001). Patients living in the West census region were 2.0 times more likely to undergo APBI compared to patients living in the Northeast (OR 2.0, 95 % CI 1.93-2.15, p < 0.001). Using the American Society of Radiation Oncology (ASTRO) guidelines, among patients with noninvasive cancer who received APBI, 95.6 % were categorized as "cautionary" and 4.4 % as "unsuitable." Of the invasive patients, 43.8 % were categorized as "suitable," 47.0 % as "cautionary," and 9.2 % as "unsuitable.", Conclusions: The utilization of APBI has stabilized at approximately 12 % starting in 2008. The majority of APBI is delivered using APBI-b, with patient age being the most significant factor associated with APBI use.

The objective of this study was to investigate the method of the combination of radiological and textural features for the differentiation of malignant from benign solitary pulmonary nodules by computed tomography. Features including 13 gray level co-occurrence matrix textural features and 12 radiological features were extracted from 2,117 CT slices, which came from 202 (116 malignant and 86 benign) patients. Lasso-type regularization to a nonlinear regression model was applied to select predictive features and a BP artificial neural network was used to build the diagnostic model. Eight radiological and two textural features were obtained after the Lasso-type regularization procedure. Twelve radiological features alone could reach an area under the ROC curve (AUC) of 0.84 in differentiating between malignant and benign lesions. The 10 selected characters improved the AUC to 0.91. The evaluation results showed that the method of selecting radiological and textural features appears to yield more effective in the distinction of malignant from benign solitary pulmonary nodules by computed tomography.

A mimic of phosphorylated prolactin (S179D PRL) inhibits mouse normal mammary HC11 cell proliferation through the upregulation of the vitamin D receptor (VDR) and p21. Here, we investigated whether S179D PRL also inhibited growth of human breast cancer MCF7 cells via VDR and p21. Western blots showed that S179D PRL upregulated VDR and p21 after the cells were incubated with S179D PRL for 3 days. These effects were blocked by the MAP kinase blocker PD98059 (25 μM), indicating that MAPK plays a role in VDR and p21 upregulation. To confirm whether VDR contributes to p21 upregulation, we used two constructs that express luciferase. One (p21 VDRE Luc) has the vitamin D response element (VDRE) in the p21 promoter region; the other (p21 NO-VDRE Luc) does not. The results show that S179D PRL upregulated p21 VDRE Luc activity in p21 VDRE Luc-transfected cells more than in p21 NO-VDRE-transfected cells, indicating that S179D PRL upregulated p21 via VDR. A cell proliferation assay showed that S179D PRL inhibits cell proliferation in a dose-dependent manner.

Background: BRCA1 recurrent mutations have rarely been assessed in non-founder populations. Still, identifying such mutations could be important for designing genetic testing strategies for high-risk breast/ovarian cancer families in non-founder populations., Objective: To determine whether the recurrent BRCA1 Y101X mutation identified in Yoruban breast cancer patients represents a single historical mutation event, and determine the prevalence of this mutation in a hospital based cohort., Methods: 365 breast cancer patients and 177 controls of Yoruban ancestry from Nigeria, unselected for age of onset or family history were screened for the BRCA1 Y101X mutation. The haplotypes on which the Y101X mutation occurred were characterized using microsatellite markers and single-nucleotide polymorphisms (SNPs). Phase ambiguity was resolved using allele-specific PCR., Results: The BRCA1 Y101X mutation was detected in four Yoruban patients with no documented family history of breast cancer among a cohort of 365 (1.1, 95% C.I. = 0.43-2.78%) unrelated Yoruban breast cancer patients. This study reveals the four Y101X mutations occur on a single, rare haplotype. Further characterization in a patient of European ancestry with a strong family history of breast/ovarian cancer revealed the same Y101X mutation on the same haplotype as those in the Yoruban carriers. These observations suggest the Y101X mutations identified in the Yoruban patients may have originated from a single mutation event., Conclusions: BRCA1 Y101X is the first reported recurrent mutation occurring in patients of African ancestry for which prevalence has been determined. Identification of this mutation in a woman of European ancestry with strong family history of breast/ovarian suggests further that this mutation occurred once, probably many generations ago.