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Inverse planning simulated annealing (IPSA) produces highly conformal dose distributions and quick optimizations for high-dose-rate interstitial brachytherapy (HDRBT). We report our dosimetry and overall outcomes using this approach for the accelerated post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue (OTSCC) with high risk of local recurrence.Patients with newly diagnosed pN0 OTSCC treated with partial glossectomy, neck dissection, and post-operative HDRBT alone from 2007 to 2021 were retrospectively reviewed. Patients received 30 Gy in 5 fractions over 2.5 days. Target volume and mandible dosimetry are reported. Actuarial rates of local control, regional control, disease-specific survival, and overall survival were estimated using the Kaplan-Meier method. Toxicity was categorized using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.19 consecutive patients were reviewed. Median follow-up was 3.2 years (IQR 1.4-8.2 years) with a 3-year estimated local control rate of 81%. Target volumes were generally small, as the median volume was 12.66 cc. Median V150% and V200% were 52% and 24%, respectively. D1cc and D2cc to the mandible were 17.31 Gy and 14.42 Gy, respectively.IPSA-HDRBT is feasible and highly efficient for post-operative treatment of the primary tumor bed in patients with pathologically node-negative squamous cell carcinomas of the oral tongue. Further technical optimization and prospective clinical evaluation in a larger patient cohort are planned.

Purpose: Increased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial. Experimental Design: HNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed. Results: Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line–derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation. Conclusions: Ruxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.

Stadt ist für mich der Raum der Akkumulation – von Besitz, Kontrolle und Gewalt – sowie von Geschichte, Widerstand und Selbstbestimmung. Diese Aspekte akkumulieren sich in der Stadt und verdichten mal mehr oder weniger gesellschaftliche (Ungleichheits)verhältnisse, die intersektional verschränkt und durch koloniale, eurozentristische, patriarchale und ableistische Normvorstellungen strukturiert sind, die sowohl reproduziert als auch gestört werden.

In the framework of the OECD/NEA/CSNI/WGAMA, an activity on the “Status report on thermal–hydraulic passive systems design and safety assessment” has been conducted. Within this activity, a benchmark exercise, based on the experimental data developed in the full scale PERSEO (in-Pool Energy Removal System for Emergency Operation) component separate effect test facility, built at SIET (Piacenza, Italy), has been proposed and carried out. An “OPEN” benchmark exercise, hosted by ENEA, has been conducted. Twelve results from eleven Organizations were submitted. PERSEO is a full-scale separate effect test facility designed to study a new passive decay heat removal system operating in natural circulation. Test 7 is a full pressure test (7 MPa) and investigates the system stability and the system operation. The accuracy of the calculated results has been evaluated both qualitatively and quantitatively. The latter has been conducted adopting the Fast Fourier Transform Based Method. The present paper summarizes the main features of the PERSEO facility and Test 7 and discusses the main results and outcome of the benchmark exercise.

Summary of sequence analysis of adenoid cystic carcinoma.

Axonal guidance signaling pathway alterations in adenoid cystic carcinoma.

Purpose:Increased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial.Experimental Design:HNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed.Results:Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line–derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation.Conclusions:Ruxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.

Supplementary Data from STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer

Supplementary Figure from STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer

Supplementary Data from TKTL1 Is Activated by Promoter Hypomethylation and Contributes to Head and Neck Squamous Cell Carcinoma Carcinogenesis through Increased Aerobic Glycolysis and HIF1α Stabilization

Purpose: This study aims to investigate the role of the aberrant expression of Transkelolase-like 1 (TKTL1) in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1α stabilization.Experimental Design: TKTL1 promoter hypomethylation and mRNA/protein aberrant expression were studied in human HNSCC tumor samples and normal mucosas. Oncogenic functions of TKTL1 were examined in HNSCC cell line panels and tumor xenograft models with TKTL1 expression construct. The metabolite levels of fructose-6-phosphate, glyceraldehydes-3-phosphate, pyruvate, lactate, and the levels of HIF1α protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells. Meanwhile, the effects of HIF1α/glycolytic inhibitors were evaluated on the TKTL1 transfectants.Results: TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal mucosas, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate, resulting in the normoxic stabilization of the malignancy-promoting transcription factor HIF1α and the upregulation of downstream glycolytic enzymes. Notably, the reduction of TKTL1 expression decreased HIF1α accumulation and inhibition with HIF1α and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression.Conclusion: TKTL1 is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1α accumulation. Clin Cancer Res; 16(3); 857–66

Supplementary Table S4 provides information on the spectra of mutations seen in MEC tumors of varying histologic grades.

Purpose:Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared with 30% of those with similar HPV-negative cancer. Loss of TGFβ signaling is a poorly studied consequence of HPV that could contribute to patient outcome by compromising DNA repair.Experimental Design:Human HNSCC cell lines (n = 9), patient-derived xenografts (n = 9), tissue microarray (n = 194), TCGA expression data (n = 279), and primary tumor specimens (n = 10) were used to define the relationship between TGFβ competency, response to DNA damage, and type of DNA repair.Results:Analysis of HNSCC specimens in situ and in vitro showed that HPV associated with loss of TGFβ signaling that increased response to radiation or cisplatin. TGFβ suppressed miR-182, which inhibited both BRCA1, necessary for homologous recombination repair (HRR), and FOXO3, required for ATM kinase activity. TGFβ signaling blockade by either HPV or inhibitors released miR182 control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the HRR deficit in HPV-positive cells. Loss of TGFβ signaling unexpectedly increased repair by error prone, alternative end-joining (alt-EJ).Conclusions:HPV-positive HNSCC cells are unresponsive to TGFβ. Abrogated TGFβ signaling compromises repair by HRR and increases reliance on alt-EJ, which provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFβ’s role in DNA repair proficiency and further raises the translational potential of TGFβ inhibitors in cancer therapy.

Figure S1 contains representative images of cells with and without the MECT1-MAML2 translocation, as determined by fluorescence in situ hybridization.

Supplemental data

List of 109 validated junctions associated with splice variants with location, gene symbol and category.

Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis and outlier statistics on RNA sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC. In ACC cells and patient-derived xenografts, FGFR1 was a uniquely expressed ASE. Detailed PCR analysis identified three novel, truncated, intracellular domain-lacking FGFR1 variants (FGFR1v). Cloning and expression analysis suggest that the three FGFR1v are cell surface proteins, that expression of FGFR1v augmented pAKT activity, and that cells became more resistant to pharmacologic FGFR1 inhibitor. FGFR1v-induced AKT activation was associated with AXL function, and inhibition of AXL activity in FGFR1v knockdown cells led to enhanced cytotoxicity in ACC. Moreover, cell killing effect was increased by dual inhibition of AXL and FGFR1 in ACC cells. This study demonstrates that these previously undescribed FGFR1v cooperate with AXL and desensitize cells to FGFR1 inhibitor, which supports further investigation into combined FGFR1 and AXL inhibition as an effective ACC therapy.This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor suggestive of a potential resistance mechanism in ACC.Significance:This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor, suggestive of a potential resistance mechanism in ACC.

Cell line authentication for SKN3

Supplemental Data S1 provides description on the ACC-01-XP xenograft development using ACC-01 cell line and shows list of PCR primers and other reagents used in the study. Supplemental Data S2 shows list of alternative splicing events identified in ACC compared to normal salivary gland tissue. Supplemental Data S3 shows nucleotides and corresponding amino acid composition of the three novel FGFR1 splice variants. Figure S1 shows ASE genes in PI3K-AKT signaling pathway enrichment using the Enrichr web tool. Figure S2 shows characterization of FGFR1v and impact on cell growth following siRNA-mediated knockdown. Figure S3 shows FGFR1v stability analysis and its effect on signaling and resistance to FGFR1 inhibitor. Figure S4 shows FGFR1v-mediated AKT signaling is independent on EGFR but supports the involvement of AXL. Figure S5 shows supportive expression and activities of FGFR1v in HACC-2A cells.

The incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) has increased more than 200% in the past 20 years. Recent genetic sequencing efforts have elucidated relevant genes in head and neck cancer, but HPV-related tumors have consistently shown few DNA mutations. In this study, we sought to analyze alternative splicing events (ASE) that could alter gene function independent of mutations. To identify ASE unique to HPV-related tumors, RNA sequencing was performed on 46 HPV-positive OPSCC and 25 normal tissue samples. A novel algorithm using outlier statistics on RNA-sequencing junction expression identified 109 splicing events, which were confirmed in a validation set from The Cancer Genome Atlas. Because the most common type of splicing event identified was an alternative start site (39%), MBD-seq genome-wide CpG methylation data were analyzed for methylation alterations at promoter regions. ASE in six genes showed significant negative correlation between promoter methylation and expression of an alternative transcriptional start site, including AKT3. The novel AKT3 transcriptional variant and methylation changes were confirmed using qRT-PCR and qMSP methods. In vitro silencing of the novel AKT3 variant resulted in significant growth inhibition of multiple head and neck cell lines, an effect not observed with wild-type AKT3 knockdown. Analysis of ASE in HPV-related OPSCC identified multiple alterations likely involved in carcinogenesis, including a novel, functionally active transcriptional variant of AKT3. Our data indicate that ASEs represent a significant mechanism of oncogenesis with untapped potential for understanding complex genetic changes that result in the development of cancer. Cancer Res; 77(19); 5248–58. ©2017 AACR.

R code for splice variant analysis and outlier statistics for identification of significant splice variants

Summary of sample cohort clinical data in tumors and normal samples including age, gender, race, smoking history, TNM stage, recurrence, follow up time, survival and HPV status

SFigure 1. Distribution of ASEs present within each tumor. SFigure2. AKT3 splice variant expression by qRT-PCR in a panel of 20 cell lines. SFigure 3. Western blot analysis of canonical AKT1 pathway after transient knockdown of AKT3 splice variant. SFigure 4. Correlation of AKT3 splice variant with other PI3K/AKT pathway mutations in TCGA.

Purpose: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.Experimental Design: Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.Results: TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (P = 0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).Conclusions: Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of MEC. Clin Cancer Res; 23(1); 283–8. ©2016 AACR.

Cell line authentication for UM-SCC-047

Purpose: To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC).Experimental Design: We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC).Results: Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04).Conclusions: These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application. Clin Cancer Res; 21(1); 30–38. ©2015 AACR.

External cephalic version (ECV) is a technique used to reduce the incidence of cesarean deliveries due to malpresentation. Nitrous oxide is an inhaled analgesic that may be used for pain relief for women undergoing external cephalic version.To compare the conversion rate of non-cephalic to cephalic presentation in ECV with and without nitrous oxide.A retrospective cohort analysis was performed including all singleton, term gestation ECVs between January 2016 and June 2017 at a single institution. Multivariable logistic regression was used to compare women who had ECV with nitrous oxide versus ECV without nitrous oxide. The primary outcome was successful rate of conversion to cephalic presentation and the secondary outcome was the rate of vaginal delivery.During the study period, 167 women underwent ECV: 77 with nitrous oxide and 90 without nitrous oxide. Of the 77 women who used nitrous oxide, 25 (32.5%) were successful and 17 of these women delivered vaginally (68%). Of the women who underwent ECV without nitrous oxide, 29 (32.2%) successfully converted and 21 of these delivered vaginally (72%). After controlling for confounders, the use of nitrous oxide had no clinically or statistically significant difference on ECV success rates (OR 1.08, 95% CI 0.52-2.23).Nitrous oxide does not seem to affect conversion rate to cephalic presentation in ECV. Further studies are needed to determine the impact of nitrous oxide on women's decision to undergo ECV and on patient satisfaction and tolerability.

The factors that contribute to postoperative trismus after mandibulectomy and fibula free flap reconstruction (FFFR) are undefined. We retrospectively assessed postoperative trismus (defined as a maximum interincisal opening ≤35 mm) in 106 patients undergoing mandibulectomy with FFFR, employing logistic regression to identify risk factors associated with this sequela. The surgical indication was primary ablation in 64%, salvage for recurrence in 24%, and osteonecrosis in 12%. Forty-five percent of patients had existing preoperative trismus, and 58% of patients received adjuvant radiation/chemoradiation following surgery. The overall rates of postoperative trismus were 76% in the early postoperative period (≤3 months after surgery) and 67% in the late postoperative period (>6 months after surgery). Late postoperative trismus occurred more frequently in patients with ramus-involving vs. ramus-preserving posterior mandibulotomies (82% vs. 46%, p = 0.004). A ramus-involving mandibulotomy was the only variable significantly associated with trismus >6 months postoperatively on multivariable logistic regression (OR, 7.94; 95% CI, 1.85–33.97; p = 0.005). This work demonstrates that trismus is common after mandibulectomy and FFFR, and suggests that posterior mandibulotomies that involve or remove the ramus may predispose to a higher risk of persistent postoperative trismus.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents — cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR — in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

The Asian-Australasian Association of Animal Production Societies (AAAP), the only international scientific organization in animal science representing Asia and Pacific region, showed a remarkable development since its inception in 1980. The number of member countries increased from 8 to 19 while 19 congresses were held in 11 different member countries. The AAAP also helped creating the official journal, Asian-Australasian Journal of Animal Sciences in 1988 with the title being changed to Animal Bioscience in 2021. It is an open access journal indexed by most global databases and has become one of the most respected global journals in animal science. Through scientific meetings and journal publication, the AAAP has made a tremendous contribution to the advancement of animal science and industry throughout its member countries over the last 40 years. This paper summarizes the advances in animal science in the Asia–Pacific region, together with the roles of the AAAP scientists and journals in developing animal science.

Introduction/Objective Increased expression of CD47 by cancer cells inhibits macrophages' phagocytic activity through CD47-SIRPα interactions, allowing evasion of the innate immune system. Several drugs on the market have been developed to target this interaction, including monoclonal therapeutics and fusion proteins. ALX148 is a genetically engineered SIRPα fusion protein with an inactivated Fc portion. CD47 is expressed highly on red blood cells (RBC), resulting in strong interference in pre-transfusion compatibility testing of patients receiving ALX148. Consequently, trial patients are at increased risk of transfusion-related adverse events or delay of needed transfusion. Few resolutions of ALX148 interference to assess underlying alloantibody development have been reported. One such examiniation demonstrated x6 linear papain-treated RBC adsorptions removed ALX148 interference. This study aimed to replicate these findings. Methods/Case Report Three patients receiving combination ALX148 (dose 6.57-20mg/mL) and Azacitidine therapy with broad-reactive RBC antibody reactivity were selected. High volume alloadsorptions (8:1 RBC:plasma) were performed with papain-treated rr (ccdee) RBCs. Adsorptions were incubated at 37C for 10 minutes. Polyethylene glycol (PEG) was utilized in test tube indirect antiglobulin testing (IAT). Results (if a Case Study enter NA) Initial reactivity strength was 3-4+ at PEG-IAT and saline-IAT with a three-cell screening RBC reagent. Alloadsorbed plasma was non-reactive at IAT with a three-cell screening RBC reagent enhanced by PEG. Drug interference was removed following three times high volume papain-treated alloadsorption. Conclusion Cancer immunotherapies have transformed the standard of care in oncology. Despite the evident clinical success, the medical laboratory has been challenged with adapting to cancer drug therapies capable of causing interference in routine laboratory testing. Clinical trials of ALX148 are associated with interference in pre-transfusion compatibility testing. The use of extended phenotype matching for RBC transfusion can be utilized but incurs additional time and resources. These results suggest high volume linear papain RBC alloadsorptions may be incorporated into antibody resolution for patients receiving ALX148.

Background: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics. Methods: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined. Results: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46–1.70] and 1.04 (95% CI, 0.96–1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53–0.90). Conclusions: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types. Impact: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3

The field of Submodular Maximization subject to a Knapsack constraint has recently expanded to a variety of application domains, which is facing some challenges such as data explosions or additional conditions. There exist plenty of objective functions that cannot be evaluated exactly in many real cases unless they are estimated with errors. It leads to solving the problem under noise models. Somewhat surprisingly, Submodular Maximization subject to a Knapsack constraint under Noise models ([Formula: see text]) has never been discussed a lot before. Hence, in this paper, we consider the problem with two kinds of noise models which are addition and multiplication. Inspired by the traditional Greedy algorithm, we first propose a Greedy algorithm under Noises with provable theoretical bounds. In order to find the solution when input data are extremely large, we then devise an efficient streaming algorithm that scans only a single pass over the data and guarantees theoretical approximations. Finally, we conduct some experiments on Influence Maximization problem under knapsack constraint, an instance of [Formula: see text] to show the performances of the proposed algorithms.

To improve timely access to quality HIV research data, the Rakai Health Sciences Program (RHSP) Data Mart was developed to store cohort study data from a legacy database platform in a modernized system using standard data management processes. The RHSP Data Mart was developed on a Microsoft SQL Server platform using Microsoft SQL Server Integration Services with custom data mappings and queries. The data mart stores 20+ years of longitudinal HIV research data and includes standard processes for managing data, data dictionary, training materials, and a library of queries to fulfill data requests and load new data from completed survey rounds. The RHSP Data Mart enables efficient querying and analysis of multidimensional research data by simplifying data integration and processing. A sustainable database platform with well-defined data management processes promotes data accessibility and reproducibility, enabling researchers to advance their understanding and management of infectious diseases.

Previous studies on the relationship of bisphenol-A (BPA) with fractional exhaled nitric oxide (FeNO) had conflicting results, suggesting that other factors may modulate this relationship. Thus, we investigated the modulating effect of vitamin D on the relationship of BPA with FeNO in children.This study recruited 432 children (10 to 12 years old) from the general pediatric population of Korea between June and July 2017. We conducted measurements of urinary BPA, serum vitamin D, specific serum IgE, FeNO, and data from impulse oscillometry (reactance area [AX], airway resistance at 5 Hz [Rrs5] and 20 Hz [Rrs10], and the difference of Rrs5 and Rrs20 [Rrs5-20]).Serum vitamin D (adjusted β =- 0.014, p=0.002) and urinary BPA (β = 0.006, p0.001) level was significantly associated with FeNO. Urinary BPA level was significantly associated with FeNO in children with low vitamin D levels (≤23 ng/mL; αβ = 0.006, p0.001), but not in children with high vitamin D levels (23 ng/mL). The interaction of vitamin D and BPA had a significant effect on FeNO (pint = 0.005). There was no relationship with the airway lung function (Rrs5, AX, and Rrs5-20) to serum vitamin D and urinary BPA level. Vitamin D ameliorated the BPA-mediated increase of FeNO in children.These results suggest that children with low vitamin D levels may be more susceptible to airway inflammation due to BPA.

Recent rapid thinning of West Antarctic ice shelves are believed to be caused by intrusions of warm deep water that induce basal melting and seaward meltwater export. This study uses data from three bottom-mounted mooring arrays to show seasonal variability and local forcing for the currents moving into and out of the Dotson ice shelf cavity. A southward flow of warm, salty water had maximum current velocities along the eastern channel slope, while northward outflows of freshened ice shelf meltwater spread at intermediate depth above the western slope. The inflow correlated with the local ocean surface stress curl. At the western slope, meltwater outflows followed the warm influx along the eastern slope with a ~2–3 month delay. Ocean circulation near Dotson Ice Shelf, affected by sea ice distribution and wind, appears to significantly control the inflow of warm water and subsequent ice shelf melting on seasonal time-scales.

We reveal three new discoveries in black hole physics previously unexplored in the Hawking era. These results are based on the remarkable 1971 discovery of the irreducible mass of the black hole by Christodoulou and Ruffini, and subsequently confirmed by Hawking. (1) The Horizon Mass Theorem states that the mass at the event horizon of any black hole — neutral, charged, or rotating — is always twice its irreducible mass observed at infinity. (2) The External Energy Theorem asserts that the rotational energy of a Kerr black hole exists completely outside the horizon. This is due to the fact that the irreducible mass does not contain rotational energy. (3) The Moment of Inertia Theorem shows that every black hole has a moment of inertia. When the rotation stops, the irreducible mass of a Kerr black hole becomes the moment of inertia of a Schwarzschild black hole. This is recognized as the rotational equivalent of the rest mass of a moving body in relativity. Thus after 50 years, the irreducible mass has gained a new and profound significance. No longer is it a limiting value in rotation, it determines black hole dynamics and structure. What is believed to be a black hole is a mechanical body with an extended structure. Astrophysical black holes are likely to be massive compact objects from which light cannot escape.

Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Despite EGFR expression in the majority of HNSCC tumors, the levels of total or phosphorylated EGFR have not consistently been correlated with a response to EGFR targeting agents. The lack of predictive biomarkers represents a major obstacle to successful use of these drugs. Activation of phosphatidylinositol 3-kinase (PI3K) signaling by mutation of the PIK3CA oncogene represents a plausible mechanism for EGFR inhibitor drug resistance. We compared the impact of EGFR inhibitors, alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs), in preclinical HNSCC models harboring mutant versus wild-type PIK3CA. Our results demonstrate additive or synergistic effects of NSAIDs and EGFR inhibitors in vitro and in vivo in PIK3CA-mutated HNSCC models. These findings suggest that the addition of NSAIDs to EGFR inhibitors for the treatment of HNSCC may represent a promising therapeutic strategy in PIK3CA-mutated cancers.