bluuebunny/crossref_metadata_2025 huggingface dataset:
An Applied Image Cryptosystem on Moore’s Automaton Operating on δ (

q
k

)/𝔽
2
Authors: Deb Subhrajyoti , Das Abhilash , Kar Nirmalya
Published: August 2023

The volume of multimedia-based image data or video frames in Web 3.0 is constantly increasing, owing to the advancement of real-time data transmission. However, security vulnerabilities frequently impair the performance of real-time applications. Many researchers have recently proposed image encryption schemes based on a high-dimensional chaotic system due to properties such as ergodicity and initial state sensitivity. Nonetheless, most schemes have suffered from excessive computational complexity, low security, and the generation of cryptographically secure random numbers. To overcome these challenges, an efficient and highly secure cryptosystem is necessary for safe multimedia transmission in Web 3.0. This article proposes a novel work on the image cryptosystem based on the
Escalation
function with a one-time key-oriented Moore’s Automaton over a finite field 𝔽
2
. The
Escalation
function is a nonlinear scrambling technique for plaintext images that goes through the confusion phase and plays an essential role in row-column permutation. To make the algorithm more secure and robust in the diffusion phase, the proposed Moore’s Automaton produced ciphertext images through a highly random key stream generated by the combination of a logistic map and cyclic group. Specifically, the proposed Moore’s Automaton operates on δ (

q
k

)/𝔽
2
to render random binary bits into unpredictable sequences to construct ciphertext images. Our new finding quickens the speed and provides adequate key space, and pixel distributions are more uniform, have high entropy value, and are secure against differential and statistical attacks.
Neurological Effects of Combining Low Toxic Dose of Tramadol and Nicotine: An Animal Model Evidence of Endoplasmic Reticulum Stress
Authors: Ghorab Doaa , Abu-El-Rub Ejlal M. , Gharaibeh Mohamed Hamdi , Yehya Alaa , Khasawneh Ramada R. , Matalqah Laila M. , Helaly Ahmed Mohamed
Published: August 2023

Tramadol abuse is a common problem in the Middle East in conjunction with smoking. The current study applied immunohistochemistry, western blot, real‐time PCR, and ELISA to test the combination toxicity. Low toxic doses of tramadol induced animal brain cortex inflammation and hippocampus injury. Adding nicotine reverted hippocampus pathological changes without triggering marked brain injury. The expression of CHOP protein with real‐time PCR showed mild endoplasmic reticulum stress (ER) in rat’s brain. Histological, immunohistochemical, and western blotting analysis of CHOP (CCAAT‐enhancer‐binding protein homologous protein) and BIP (immunoglobulin heavy chain‐binding protein) chaperones demonstrated endoplasmic reticulum stress in the brains of animals. Furthermore, the levels of apoptosis and autophagy markers demonstrated a mild reaction. The blood level of serotonin was high in all study groups, with a marked increase in the combined one. The high serotonin levels in the blood can be critical and associated with a high risk of serious withdrawal and pathological consequences. Serotonin receptor blockers such as olanzapine may increase systemic serotonin levels and need further investigation to utterly pinpoint their roles in managing mood disorders. In conclusion, the combination of tramadol and nicotine is less harmful than expected. However, serious withdrawal effects can occur as a result of high systemic serotonin effects.
Toughness Enhancement of PLA-Based Filaments for Material Extrusion 3D Printing
Authors: Pongsathit Siriwan , Kamaisoom Jutamas , Rungteerabandit Atikarn , Opaprakasit Pakorn , Jiamjiroch Krit , Pattamaprom Cattaleeya
Published: August 2023

Poly(lactic acid) (PLA) is one of the most popular biodegradable thermoplastics in the market of 3D printing filaments used in the material extrusion (ME) technique. This is because it can be printed easily at low temperatures. However, its inherent brittleness limits its use in many applications. In this work, the toughness of PLA filament was improved by blending with various types of rubbers including natural rubber (NR), acrylic core–shell rubber (CSR), and thermoplastic polyurethane (TPU) in the amount of 15% by weight. PLA/TPU filament was found to have the smoothest surface with the best shape and dimension stability, while PLA/NR filament rendered the highest tensile toughness. In term of the effect of printing temperature, the highest printing temperature in this study (210°C) provided the highest smoothness with the best shape stability and dimension accuracy. Interestingly, the tensile toughness and elongation at break of 3D printed specimens were found to be higher than those of compression-molded specimens for all filament types. This could be explained by the ability of the 3D printing technique to produce specimens that aligned in the printing direction in a fiber-like pattern.
Novel Predictive Scoring System for Intravenous Immunoglobulin Resistance Helps Timely Intervention in Kawasaki Disease: The Chinese Experience
Authors: Wang Yan , Huang Shuoyin , Wang Panpan , Wu Yan , Liu Yingying , Pan Yuting , Dong Jinyuan , Fan Zhidan , Yu Haiguo
Published: August 2023

Background. Approximately 10%–20% of patients with Kawasaki disease (KD) are nonresponsive to intravenous immunoglobulin (IVIG) treatment, placing them at higher risk of developing coronary heart lesions. Early detection of nonresponsiveness is crucial to curtail this risk; however, the applicability of existing predictive scoring systems is limited to the Japanese population. Our study aimed to identify a predictive scoring system for IVIG resistance in KD specific to the Chinese population. We aimed to assess the utility of three commonly used risk-scoring systems in predicting IVIG resistance and compare them to the newly developed predictive scoring system. Methods. A total of 895 patients with KD were enrolled in this retrospective review and divided into two groups: IVIG responders and nonresponders. Clinical and laboratory variables were compared between the two groups. Multivariable logistic regression models were used to construct a new scoring system. The utility of the existing and new scoring systems was assessed and compared using the area under the receiver operating characteristic curve. Results. Albumin levels, percentage of neutrophils, and hemoglobin were independent predictors of resistance by logistic regression analysis. The new predictive scoring system was derived with improved sensitivity (60.5%) and specificity (87.8%). The area under the receiver operating characteristic curve was 0.818. Conclusion. This study developed a novel risk-scoring system for predicting resistance to IVIG treatment in KD specific to the Chinese population. Although this new model requires further validation, it may be useful for improving prognostic outcomes and reducing the risk of complications associated with KD.
Some Traveling Wave Solutions to the Fifth-Order Nonlinear Wave Equation Using Three Techniques: Bernoulli Sub-ODE, Modified Auxiliary Equation, and

G

′

/
G

-Expansion Methods
Authors: Ali Khalid K. , Alotaibi Maged Faihan , Omri Mohamed , Mehanna M. S. , Abdel-Aty Abdel-Haleem
Published: August 2023

The fifth-order nonlinear wave equation contains terms involving higher-order spatial derivatives, such as

u

x
x
x

and

u

x
x
x
x
x

. These terms are responsible for dispersion, which affects the shape and propagation of the wave. The study of dispersion is important in many areas, including seismology, acoustics, and communication theory. In the current work, three potent analytical techniques are proposed in order to solve the fifth-order nonlinear wave equation. The used approaches are the modified auxiliary equation method, the Bernoulli Sub-ODE method, and the

G

′

/
G

-expansion method (MAE). Some graphs are plotted to display our findings. The solutions to the nonlinear wave equation are used to describe the nonlinear dynamics of waves in physical systems. The results show how the dynamics of the wave solutions are influenced by the system parameters, which can be used as system controllers. The new approaches used in this work helped to find new solutions for traveling waves. This could be seen as a new contribution to the field. Water waves, plasma waves, and acoustic wave behavior can be described by the obtained solutions.
Gambogic Acid Inhibits Gastric Cancer Cell Proliferation through Necroptosis
Authors: Wang Shujun , Wang Yiping , Zhu Hui , Chen Miaohui , Zhang Liang
Published: August 2023

Gambogic acid (GA) is a natural xanthonoid secreted by Garcinia hanburyi tree. It possesses anti-cancer activity in various types of cancers. In gastric cancer, it inhibits cell proliferation through increasing apoptosis. However, whether necroptosis is involved in the GA-induced proliferation inhibited in gastric cancer is unknown. In the present study, we found that RIPK1 specific inhibitor necrostatin-1 (Nec-1) attenuated GA-induced proliferation inhibition. GA treatment increased the phosphorylation of necroptosis-related proteins, RIPK1, RIPK3, and MLKL, and their interactions to form the necrosome complex. The effector protein Drp-1 was dephosphorylated by GA treatment. Inhibition of necroptosis by different inhibitors and PGAM5 knockdown attenuated GA-induced cell death in gastric cancer cell lines, thereby attenuating GA-caused cell proliferation inhibition. All the data supported the conclusion that GA could inhibit gastric cancer cell proliferation by inducing necroptosis.
Effect of Ferrule Location on Fracture Resistance of Maxillary Premolars: An In Vitro Study
Authors: Koosha Sara , Jebelizadeh Mahdieh S. , Mostafavi Azam S.
Published: August 2023

Objectives. The present study aimed to assess the effect of ferrule location on fracture resistance of maxillary premolars. Materials and Methods. A total of 72 extracted human maxillary premolars were selected and randomly assigned to six groups (n = 12 in each) considering ferrule location: circumferential ferrule (CF), without ferrule (WF), buccal ferrule (BF), lingual ferrule (LF), mesial ferrule (MF), and buccal–lingual ferrule (BLF). Cast posts were cemented into the prepared post spaces. Following conventional impression, Ni–Cr crowns were cemented to the specimens. After thermocycling (5,000 cycles, 5–55°C), the specimens were loaded at 45° in a universal testing machine until fracture. Data were analyzed with one-way ANOVA, Kolmogorov–Smirnov, and Tamhane tests. Results. The maximum and minimum mean fracture resistance were related to the CF (1,143.84 N) and WF (514.89 N) groups, respectively, (P=0.039). Fracture resistance in the BF (933.67 N) and BLF (874.01 N) groups was significantly higher than in the MF group (617.54 N) (P=0.001). There was no significant difference between the MF, LF (722.89 N), and WF groups in terms of fracture resistance (P>0.05). Conclusion. Teeth with CF showed maximum fracture resistance. The location of the ferrule effects on the fracture resistance of maxillary premolars and also the mode of failure.
Supplementary Table S1 from Racial and Ethnic Variation in Diagnostic Mammography Performance among Women Reporting a Breast Lump
Authors: Nyante Sarah J. , Abraham Linn , Aiello Bowles Erin J. , Lee Christoph I. , Kerlikowske Karla , Miglioretti Diana L. , Sprague Brian L. , Henderson Louise M.
Published: August 2023

Raw numbers for performance statistic calculations
Supplemental Table 3 from Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: August 2023

Supplemental Table 3: Mutation frequencies in invasive ovarian cancer cases and controls and risk of ovarian cancer in the NHS, NHSII, and CPSII
Supplemental Table 2 from Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: August 2023

Supplemental Table 2: Mutation frequencies in ovarian cancer cases and controls and risk of ovarian cancer in the NHS, NHSII, and CPSII cohorts combined
Supplemental Figure 1 from Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: August 2023

Supplemental Figure 1: Kaplan-Meier survival curves for all-cause mortality among cases with Type II tumors (high/unknown grade serous, poorly differentiated, or high grade endometrioid) for A) BRCA1 mutation carriers, B) BRCA2 mutation carriers (solid black lines). Grey lines are women with no mutation in any of the measured high-penetrance genes. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox Proportional hazard models and were adjusted for age at diagnosis (continuous), year of ovarian cancer diagnosis (continuous), and stage (0, I, II, III, IV, Unknown)
Data from Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: August 2023

AbstractBackground:
With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies [Nurses’ Health Study (NHS), NHSII, Cancer Prevention Study II].
Methods:
We included women with epithelial ovarian or peritoneal cancer (n = 776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n = 1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status.
Results:
The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P < 0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk [OR, BRCA1 = 12.38; 95% confidence interval (CI) = 4.72–32.45; OR, BRCA2 = 9.18; 95% CI = 3.98–21.15]. Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR = 5.79; 95% CI = 1.09–30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation.
Conclusions:
Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations.
Impact:
Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.
Table S9 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: August 2023

Quantification of Human Phospho-Proteome Array
Table S1 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: August 2023

Genes included in the CRISPR screening library
Supplementary Video S9 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S9 shows the clustering video of siALCAM1 transfected ST6KO cells presented in Fig.5E.
Supplementary Video S8 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S8 shows the clustering video of scrRNA transfected ST6KO cells presented in Fig.5E.
Supplementary Video S7 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S7 shows the clustering video of PBS treated cells presented in Fig.2E
Supplementary Video S6 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S6 shows the clustering video of PAX treated cells presented in Fig.2E.
Supplementary Video S3 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S3 shows the clustering video of ST6KO cells presented in Fig.2B.
Supplementary Figures S1-S17 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Figure S1-S17 show the methods of CTC analysis and CTC-associated survival (S1); glycosylation profiles of patient CTCs (S2); phenotypic effects of neuraminidase treatment and CD44 depletion on tumor clustering and sialylation (S3); N-glycomic analysis of α2,6-SA peaks in WT and ST6KO cells (S4); Depletion of ST6GAL1 or ST3GAL1 promotes clustering and chemo-evasion (S5); ST6GAL1 expression and cell sensitivity to therapeutics (paclitaxel, doxorubicine and palbociclib)(S6); he altered gene pathways in ST6GAL1-KO cells (S7); ST6GAL1 is associated with cell growth and patient survival (S8); dynamic glycosylation profile in PDXs and breast tumors (S9); ST6GAL1 suppresses metastatic seeding (S10); Counts and Ki67 expression of CTCs and DTCs in situ (S11); depletion of ST6GAL1 promotes transendothelial migration and seeding (S12);α2,6-sialylation of CD44 by ST6GAL1(S13); ST6GAL1 substrates regulate cluster formation via altered binding affinity (S14); the down-regulation of ST6GAL1 substrates inhibits metastatic seeding (S15); anti-PODXL inhibits tumor cell cluster formation and metastatic seeding(S16); and anti-PODXL effects on CTCs and seeding of PDX-M1 (S17).
Supplementary Excel S4 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Excel S4 shows the list of SNA-pull down glycoproteins detected via glycoproteiomics analysis
Supplementary Excel S3 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Excel S3 shows the results of RNA sequencing.
Supplementary Excel S2 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Excel S2 shows SNA binding on patient CTCs analyzed by flow cytometry.
Supplementary Excel S1 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Excel S1 shows CTC numbers of the patients analyzed by CellSearch.
Supplementary Table 1 from PARP inhibitors effectively reduce MAPK inhibitor resistant melanoma cell growth and synergize with MAPK inhibitors through a synthetic lethal interaction in vitro and in vivo
Authors: Froehlich Lisa Marie , Niessner Heike , Sauer Birgit , Kaemereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit
Published: August 2023

RT2 ProfilerTM PCR Array Human p53 Signaling Pathway and Human DNA Repair Pathway
Supplementary Figure 2 from PARP inhibitors effectively reduce MAPK inhibitor resistant melanoma cell growth and synergize with MAPK inhibitors through a synthetic lethal interaction in vitro and in vivo
Authors: Froehlich Lisa Marie , Niessner Heike , Sauer Birgit , Kaemereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit
Published: August 2023

Synergistic interaction of PARPi and MAPKi treatment
TABLE 1 from MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids
Authors: Pickles Oliver J. , Wanigasooriya Kasun , Ptasinska Anetta , Patel Akshay J. , Robbins Helen L. , Bryer Claire , Whalley Celina M. , Tee Louise , Lal Neeraj , Pinna Claudia M.A. , Elzefzafy Nahla , Taniere Philippe , Beggs Andrew D. , Middleton Gary M.
Published: August 2023

Clinicopathologic characteristics of organoids and MHC expression
Supplementary Figure 4 from MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids
Authors: Pickles Oliver J. , Wanigasooriya Kasun , Ptasinska Anetta , Patel Akshay J. , Robbins Helen L. , Bryer Claire , Whalley Celina M. , Tee Louise , Lal Neeraj , Pinna Claudia M.A. , Elzefzafy Nahla , Taniere Philippe , Beggs Andrew D. , Middleton Gary M.
Published: August 2023

Non-inducible organoids demonstrate no further upregulation of Class II following IFNγ cotreatment with Azacitidine. The three non-inducible organoids (376, 557 and 946) were treated with control or 72 hours IFNγ 75 IU/ml +/- 6 days 2 µM Azacitidine. Flow cytometry assessment of Class II upregulation from representative experiments displayed.
Figure S6 from Discovery and characterization of ZL-2201, a potent, highly selective, and orally bioavailable small-molecule DNA-PK inhibitor
Authors: Lal Shruti , Bhola Neil E. , Sun Bee-Chun , Chen Yuping , Huang Tom , Morton Vivian , Chen Kevin X , Xia Shanghua , Zhang Haoyu , Parikh Nehal S , Ye Qiuping , Veiby O. Petter , Bellovin David I , Ji Yuhua
Published: August 2023

ZL-2201 reduces DNA damage-induced MCM2 phosphorylation (Ser108).
Figure S5 from Discovery and characterization of ZL-2201, a potent, highly selective, and orally bioavailable small-molecule DNA-PK inhibitor
Authors: Lal Shruti , Bhola Neil E. , Sun Bee-Chun , Chen Yuping , Huang Tom , Morton Vivian , Chen Kevin X , Xia Shanghua , Zhang Haoyu , Parikh Nehal S , Ye Qiuping , Veiby O. Petter , Bellovin David I , Ji Yuhua
Published: August 2023

Phenotypic effects of combining ZL-2201 and Doxorubicin
Figure S1 from Discovery and characterization of ZL-2201, a potent, highly selective, and orally bioavailable small-molecule DNA-PK inhibitor
Authors: Lal Shruti , Bhola Neil E. , Sun Bee-Chun , Chen Yuping , Huang Tom , Morton Vivian , Chen Kevin X , Xia Shanghua , Zhang Haoyu , Parikh Nehal S , Ye Qiuping , Veiby O. Petter , Bellovin David I , Ji Yuhua
Published: August 2023

Synthesis of ZL-2201
Data from PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction In Vitro and In Vivo
Authors: Fröhlich Lisa Marie , Niessner Heike , Sauer Birgit , Kämereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit
Published: August 2023

The efficacy of targeting the MAPK signaling pathway in patients with melanoma is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an antimelanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage sensor ataxia-telangiectasia mutated (ATM). As a consequence, MAPK inhibitor resistant melanoma cells have decreased homologous recombination repair activity leading to a reduced repair of double-strand breaks caused by the PARP inhibitors. We validated the clinical relevance of our findings by ATM expression analysis in biopsies from patients with melanoma before and after development of resistance to MAPK inhibitors. Furthermore, we show that inhibition of the MAPK pathway induces a homologous recombination repair deficient phenotype in melanoma cells irrespective of their MAPK inhibitor sensitivity status. MAPK inhibition results in a synthetic lethal interaction of a combinatorial treatment with PARP inhibitors, which significantly reduces melanoma cell growth in vitro and in vivo. In conclusion, this study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression.
Significance:
We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. Our study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression, which could serve as a novel biomarker for treatment response.
Data from PARP inhibitors effectively reduce MAPK inhibitor resistant melanoma cell growth and synergize with MAPK inhibitors through a synthetic lethal interaction in vitro and in vivo
Authors: Froehlich Lisa Marie , Niessner Heike , Sauer Birgit , Kaemereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit
Published: August 2023

Abstract
The efficacy of targeting the MAPK signaling pathway in melanoma patients is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an anti-melanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage sensor ataxia-telangiectasia mutated (ATM). As a consequence, MAPK inhibitor resistant melanoma cells have decreased homologous recombination repair activity leading to a reduced repair of double strand breaks caused by the PARP inhibitors. We validated the clinical relevance of our findings by ATM expression analysis in biopsies from melanoma patients before and after development of resistance to MAPK inhibitors. Furthermore, we show that inhibition of the MAPK pathway induces a homologous recombination repair deficient phenotype in melanoma cells irrespective of their MAPK inhibitor sensitivity status. MAPK inhibition results in a synthetic lethal interaction of a combinatorial treatment with PARP inhibitors, which significantly reduces melanoma cell growth in vitro and in vivo. In conclusion, this study shows that PARP inhibitor treatment is a valuable therapy option for melanoma patients, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression.
Data from Discovery and Characterization of ZL-2201, a Potent, Highly Selective, and Orally Bioavailable Small-molecule DNA-PK Inhibitor
Authors: Lal Shruti , Bhola Neil E. , Sun Bee-Chun , Chen Yuping , Huang Tom , Morton Vivian , Chen Kevin X. , Xia Shanghua , Zhang Haoyu , Parikh Nehal S. , Ye Qiuping , Veiby O. Petter , Bellovin David I. , Ji Yuhua
Published: August 2023

DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation.
Significance:
ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic.
Data from Discovery and characterization of ZL-2201, a potent, highly selective, and orally bioavailable small-molecule DNA-PK inhibitor
Authors: Lal Shruti , Bhola Neil E. , Sun Bee-Chun , Chen Yuping , Huang Tom , Morton Vivian , Chen Kevin X , Xia Shanghua , Zhang Haoyu , Parikh Nehal S , Ye Qiuping , Veiby O. Petter , Bellovin David I , Ji Yuhua
Published: August 2023

Abstract
DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response (DDR) pathway, plays an instrumental role in repairing double-strand breaks (DSBs) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacological inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ATM deficiency and ZL-2201 sensitivity. Moreso, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phospho-proteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation.
Selective Removal to Soft Dentine versus Full Pulpotomy for Management of Proximal Deep Carious Lesions: A Randomized Controlled Non-Inferiority Trial
Authors: R Rechithra , Wani Wasim , Sharma Sidhartha , Kumar Vijay , Chawla Amrita , Kalaivani Mani , Logani Ajay
Published: August 2023

The management of the deep carious lesion with reversible pulpitis is a dilemma for the dentist. The current study compared selective removal to soft dentine (SRSD) and full pulpotomy (FP) for treating proximal deep carious lesions in teeth with reversible pulpitis. Visual-tactile examination and bitewing radiographs were used to determine the depth of carious lesion, and American Association of Endodontists recommendations were used to formulate pulp diagnosis. Sixty mandibular molar teeth from healthy patients between the ages of 16–35 years and a diagnosis of proximal deep carious lesion with reversible pulpitis were included. Teeth were randomly allocated to two study groups. SRSD group (n = 30): soft dentine was preserved over the pulpal aspect. A hard-setting calcium hydroxide cement liner and resin-modified glass ionomer cement base were applied over the remaining soft carious dentine. FP group (n = 30): complete caries removal followed by mineral trioxide aggregate FP was performed. The teeth in both groups were restored with composite resin restoration. The established criteria for outcome assessment of SRSD and pulpotomy were used. Accordingly, only asymptomatic teeth with no radiological evidence of periapical rarefaction were considered successful at the 12-month follow-up. Two-sample t test, Pearson χ2 test/Fisher’s exact test, and percentage agreement were used for statistical evaluation. According to the per-protocol analysis, the success rate of both SRSD and FP treatment was 95.45% and 95.65%, respectively, and the actual difference between the two treatments was 1% (95% CI: [−10, 9]). The data suggests that both treatments (SRSD and FP) appear to have a good success rate (>95%) when used to manage permanent mandibular molar teeth with proximal deep carious lesion and reversible pulpitis. As SRSD is a noninvasive procedure, it should be favored over FP in these instances.
Local Adenoviral Delivery of Vascular Endothelial Growth Factor C Induces Lymphangiogenesis in the Conjunctiva in Rabbits
Authors: Rasic Dusan , Wirenfeldt Martin , Askou Anne Louise , Corydon Thomas J. , Telinius Niklas
Published: August 2023

Introduction: The purpose of this study was to determine if conjunctival lymphangiogenesis can be induced using adenoviral delivery of vascular endothelial growth factor C (VEGF-C). Methods: Seventeen New Zealand white rabbits received a subconjunctival injection containing 3.5 × 107 plaque-forming units of an adenoviral vector containing the gene-encoding VEGF-C (Ad-VEGF-C). The contralateral eye was used for control experiment (the same volume of either saline or an empty vector). After 2 weeks, the animals were examined with trypan blue conjunctival lymphangiography, and the eyes were harvested for histology and immunohistochemistry (podoplanin and CD31). Results: Trypan blue conjunctival lymphangiography revealed significantly more extensive conjunctival vessel network in the Ad-VEGF-C group compared with control: 1.35 ± 0.67 versus 0.28 ± 0.17 vessel length/analysed area (p = <0.0001). This finding was confirmed with immunohistochemistry, where a significant increase in the number of lymphatic vessels was found compared to control; 34 ± 9 per mm2 versus 13 ± 8 per mm2 (p = 0.0019). Furthermore, there was a significant increase in lymphatic cross-sectional area; 32,500 ± 7,900 µm2 per mm2 versus 17,600 ± 9,700 µm2 per mm2 (p = 0.0149). Quantification of blood vessels revealed no significant difference in blood vessel density between Ad-VEGF-C and control; 19 ± 9 per mm2 versus 14 ± 8 per mm2 (p = 0.1971). There was no significant difference in total blood vessel area; 13,200 ± 7,600 µm2 per mm2 versus 7,100 ± 3,000 µm2 per mm2 (p = 0.0715). Eyes treated with an adenoviral vector (VEGF-C or empty vector) responded with a reactive cellular response, predominantly lymphocytes, towards the vector. Conclusion: The study demonstrates the feasibility of inducing conjunctival lymphangiogenesis with a single subconjunctival injection of Ad-VEGF-C. Future studies will explore how this can be used with a therapeutic purpose.
Ocular Characteristics of Pseudophakic Eyes with Malignant Glaucoma
Authors: Zhang Yulin , Wang Sheng , Lin Hongliang , He Beiting , Liu Yiliang , Yang Baodi , Chen Yanlei , Niu Yongyi , Qin Yongjie , Zhang Hongyang
Published: August 2023

Introduction: The aim of the study was to investigate the clinical characteristics and treatment outcomes of the pseudophakic eyes with malignant glaucoma (MG). Methods: This retrospective case-control study enrolled 53 eyes of 47 patients with primary angle-closure glaucoma having cataract surgery history, including 19 patients (25 eyes) diagnosed with MG and 28 patients (28 eyes) without MG as the match. Among patients diagnosed with MG, 14 patients (18 eyes) underwent zonulo-hyaloido-vitrectomy (ZHV) and the other 5 patients (7 eyes) received conservative treatments. The visual acuity, refraction status, intraocular pressure (IOP), extent of peripheral anterior synechia, classes of anti-glaucoma medications, and ultrasound biomicroscopy (UBM) examination were recorded before cataract surgery, at the diagnosis of MG, and 3 months after ZHV or atropine application, respectively. Results: In the pseudophakic eyes with MG, the IOP cannot be well controlled compared to the matched eyes (27.24 ± 8.72 mm Hg vs. 14.30 ± 2.63 mm Hg, p < 0.001). In addition, there was a difference in the average spherical equivalent refractive error between 2 groups of patients (−2.23 ± 0.84 D in MG vs. −0.12 ± 0.64 D in the matched eyes, p < 0.001). By UBM analysis, the anterior chamber depth (ACD) was shallower in MG than that in the matched eyes (2.34 ± 0.20 mm vs. 3.47 ± 0.29 mm, p < 0.001). The difference between the anterior vault distance of the pseudophakic eyes with MG and that of the matched eyes was also significant (p < 0.001). After treated with ZHV, the IOP was greatly decreased from 27.84 ± 10.14 mm Hg to 15.85 ± 4.41 mm Hg (p < 0.001). The refractive error also changed from −2.11 ± 0.91 D to +0.42 ± 0.99 D (p < 0.001). At the same time, the central ACD was significantly deepened from 2.30 ± 0.39 mm to 3.30 ± 0.31 mm (p < 0.001). Conclusion: Uncontrolled IOP and shallow anterior chamber both centrally and peripherally are the primary clinical characteristics for the pseudophakic eyes with MG. An unexpected refractive error or myopic shift for the eyes with PACG after cataract surgery can be an important hint for diagnosis of MG. The typical UBM image is an anterior displacement of the lens-iris diaphragm and a bow-shaped change of the intraocular lens. It is an effective way to treat pseudophakic MG with the ZHV through a peripheral iridectomy.
Clinical Evaluation of Coronally Advanced Lingual Flap for Maintaining Primary Wound Closure over Titanium Mesh After Guided Bone Regeneration: A Randomized Control Trial
Authors: Attia Rasha , El-Nahass Hani , Anis Maged , Hosny Manal
Published: August 2023

Purpose: To evaluate the clinical efficacy of the coronally advanced lingual flap (CALF) technique in terms of the extent of lingual and buccal flap advancement, the maintenance of primary wound closure, and safety in comparison to buccal flap advancement alone during horizontal ridge augmentation in the posterior mandible. Materials and Methods: A total of 14 patients were randomly allocated to two different groups: buccal flap advancement without the CALF technique (control), referred to as the NO-CALF group, and buccal flap advancement with the CALF technique (test), referred to as the CALF group. Wound healing was monitored weekly for the first 4 weeks, then at 2, 4, 6, and 9 months postoperatively for any soft tissue dehiscence (titanium mesh [TM] exposure) along the incision line. The extent of lingual and buccal flap advancement was measured, and any intraoperative and postoperative CALF-related complications were reported. Results: The difference between groups was statistically significant (P < .0001) in terms of (1) TM exposure: 83.3% of cases in the NO-CALF group showed early Class П exposures, whereas the CALF group showed no exposure; (2) mean lingual flap advancement: 3.9 ± 1.1 mm and 14.4 ± 3.8 mm for the NO-CALF and CALF groups, respectively; and (3) mean buccal flap advancement: 15.8 ± 2.1 mm and 10.5 ± 1.4 mm for the NO-CALF and CALF groups, respectively. There were no reported complications related to the CALF technique. Conclusion: Tension-free primary wound closure was facilitated and maintained during the healing period by applying the CALF technique, which is a reliable technique to safely advance the lingual flap coronally.
A Novel Screwless Modification of the Khoury Plate Technique using an Innovative Bone Adhesive Formulated from Underwater Biomimetic Marine Proteins
Authors: Pikos Michael A , Miron Richard J
Published: August 2023

Over the past two decades, the Khoury plate technique has been widely utilized with much success to facilitate bone augmentation in critically deficient bone areas. Simply, the technique includes harvesting autogenous bone plates and utilizing them with external screw fixation. The rigidity of the bone plates enclosing the bony defect on both the buccal and lingual surfaces allows for tension-free bone remodeling to occur, favoring an ideal bone-forming environment. Following, a 4- to 6-month healing period, a flap is raised, screws may be removed, and implants are placed. With advancements made in tissue engineering, a novel mineral-organic resorbable bone adhesive (MORBA) formulated from underwater biomimetic marine proteins has recently been utilized for immediate bone-to-bone or bone-to-metal fixation. MORBA is a synthetic, injectable, self-setting, and resorbable load-bearing adhesive biomaterial that exhibits over 300 pounds of fixation strength. The unique adhesive properties of MORBA enable it to immediately stabilize dental implants into host bone. The present article describes a novel modification of the Khoury plate technique that utilizes MORBA as a substitute for screws during bone plate fixation. A step-by-step protocol is described that utilizes this novel biomaterial, favoring a more biologic approach to this conventional technique. This novel modification is surgically easier to conduct and is a more biocompatible option that avoids screw fixation and removal.