Dimple Grinding Coupled with Optical Microscopy for Porosity Analysis of Metallic Coatings.

Dimple grinding is one of the steps used in a common method of preparing samples for transmission electron microscopy (TEM); the TEM sample preparation process also involves ion beam sputtering after the dimpling stage. During dimpling, a spherical depression is machined into the sample, leaving a thicker rim to support and facilitate sample handling. In this paper, an alternative application for dimple grinding is developed; dimple grinding combined with optical microscopy is utilized to quantify internal porosity present within coatings. This technique essentially permits three dimensional porosity quantification across the coating thickness using a simple polishing method which provides analysis of areas larger than those observed during standard cross sectional microscopy. The application of this technique to nine electroless nickel-phosphorus (Ni-P) coatings deposited on Mg substrates is demonstrated. An analysis linking medium P content in the Ni-P coatings and high coating thickness to lower porosity is also performed. The lowest porosity was observed for medium P content coatings (5.2 wt% P), while the largest porosity occurred for the high P content coatings (10.0 wt% P). Porosity levels decreased continuously with increasing coating thickness (from 28 µm to 57 µm).

[Alteration and significance of serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma: a retrospective study based on LEGEND-2].

Objective: To explore the dynamic changes in serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma (R/R MM) based on LEGEND-2. Methods: The data of patients with R/R MM who underwent BCMA-CAR-T therapy at our hospital between March 30, 2016, and February 6, 2018, were retrospectively collected. Serum lipid levels, controlled nutritional status (CONUT) score, and other clinical indicators at different time points before and after CAR-T-cell infusion were compared and analyzed. The best cut-off value was determined by using the receiver operator characteristic (ROC) curve. The patients were divided into high-CONUT score (>6.5 points, malnutrition group) and low-CONUT score groups (≤6.5 points, good nutrition group), comparing the progression-free survival (PFS) and total survival (OS) of the two groups using Kaplan-Meier survival analysis. Results: Before the infusion of CAR-T-cells, excluding triglycerides (TG), patients' serum lipid levels were lower than normal on average. At 8-14 d after CAR-T-cell infusion, serum albumin (ALB), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A1 (Apo A1) levels dropped to the minimum, whereas CONUT scores reached the maximum. In addition to TG, apolipoprotein B (Apo B) levels increased compared with baseline. After CAR-T-cell therapy, the patients' serum lipid levels significantly increased with well-improved nutritional status. Spearman's related analysis showed that TC, HDL, and ApoA1 levels after CAR-T-cell injection were significantly negatively correlated with the grade of cytokine-release syndrome (CRS) (r=-0.548, P=0.003; r=-0.444, P=0.020; r=-0.589, P=0.001). Furthermore, survival analysis indicated that the CONUT score was unrelated to PFS, and the median OS of patients with R/R MM in the high-CONUT score group was shorter than that in the low-CONUT score group (P=0.046) . Conclusions: During CAR-T-cell therapy, hypolipidemia and poor nutritional status were aggravated, which is possibly related to CRS. The patients' serum lipid levels and nutritional status were significantly improved after CAR-T-cell treatment. The CONUT score affected the median OS in patients treated with CAR-T-cells. Therefore, specific screening and intervention for nutritional status in patients receiving CAR-T-cell therapy are required.

Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.

Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

[The perforator flap of ipsilateral nasolabial sulcus used to repair the defect after the eradication of nasal vestibular squamous cell carcinoma].

Objective: To investigate the feasibility of only surgical resection for nasal vestibular squamous cell carcinoma and the efficacy of perforator flap of ipsilateral nasolabial sulcus in repairing postoperative defects. Methods: The clinical data of 8 cases with squamous cell carcinoma of the nasal vestibule who admitted to Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University were analyzed, including 6 males and 2 females, aged from 38 to 75 years. The tumor of the nasal vestibule was eradicated in time after making definite diagnosis of lesions, then the perforators flap of the ipsilateral nasolabial sulcus was used for repairment, without performing further chemotherapy or radiotherapy after surgery. The tumor recurrence, facial appearance, nostril form, donor area scar, nasal ventilation function, and cutaneous sensation were evaluated after surgery. Descriptive analysis was used in this research. Results: There were 2 cases of stage T1 and 6 cases of stage T2 in 8 cases. After 32 to 45 months of following-up, no recurrence accurred and all the flaps survived well. However, there was about 2 mm necrosis of the transplanted flap in the lateral foot of the alar in one case, which was healed well by carrying out wound care after 10 d. And the dark color flap was occurred in another case, showing the flap's backflow trouble, yet it was improved with addressing timely during 5 d postoperation. Pincusion-like deformity of the transplanted flap occurred in 4 cases (50%), which subsided gradually after 6 months. The morphology of the anterior nostril was altered in 4 cases (50%), but there was no ventilation trouble and no need for addressment in any case. The postoperative facial appearance was rated as excellentor good with hidden scar in the donor site, and the sensation of the transplanted flaps was indistinct from the surrounding tissue after 3 months. Conclusions: Surgical resection of nasal vestibular squamous cell carcinoma with tumor stage T1-2 is a feasible treatment. And it is the one of the best reconstructive methods of the perforator flap of the ipsilateral nasolabial sulcus to repair the deformities after the surgery.

CREB inactivation by HDAC1/PP1γ contributes to dopaminergic neurodegeneration in Parkinson's disease.

Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction occurred in the nigral dopaminergic neurons of PD patients as demonstrated using a proximity ligation assay. Disrupting CREB/HDAC1 interaction via either overexpression of GAL4 M1, a CREB mutant, or administration of trichostatin A, a pan-HDAC inhibitor, restored the expression levels of phospho-CREB (Ser133) and NURR1, and protected nigral dopaminergic neurons in the MPTP-treated mice brain. Collectively, our results demonstrated that HDAC1/PP1γ-mediated CREB inactivation contributed to dopaminergic neuronal degeneration. Disruption of CREB/HDAC1 interaction has the potential as a new approach for PD therapy.Significance StatementPD is the most common movement disorder attributed to the progressive loss of dopaminergic neurons in the substantia nigra. Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for PD. We found in nigral dopaminergic neurons of postmortem human PD brains that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. HDAC1, constitutively associated with PP1γ, interacted with CREB to mediate its dephosphorylation during dopaminergic degeneration. Disrupting CREB/HDAC1 interaction restored CREB activity and protected nigral dopaminergic neurons in the MPTP mouse brains. This work suggests that disruption of the CREB/HDAC1 interaction to restore CREB activity may be a potential therapeutic approach in PD.

[Clinical characteristics and risk factors of lower extremity arterial disease in patients with diabetic foot ulcer].

OBJECTIVE: To investigate the clinical characteristics of lower extremity arterial disease (LEAD) and its risk factors in patients with diabetic foot ulcer (DFU). METHODS: We retrospectively collected the clinical and follow-up data of 650 patients with DFU treated in the Department of Endocrinology and Metabolism of Nanfang Hospital between January, 2017 and December, 2019. We compared the data between patients who had LEAD and those without LEAD and used a multivariate logistic regression model to analyze the risk factors of LEAD in DFU patients. RESULTS: Among the 650 DFU patients, 470 (72.4%) had LEAD. The patients were followed up for a mean of 3.5 months, and the mean healing time of DFU was 2.55 months; healing of DFU occurred in 453 patients and 183 patients received amputation. The patients with LEAD and those without LEAD differed significantly in age, hospitalization costs, diastolic blood pressure (DBP), glycated hemoglobin, blood lipid levels, disease course, ankle brachial index, healing time, smoking history, clinical outcomes, Wagner grade and imaging results (P < 0.05). Multivariate logistic regression analysis identified age (OR=1.070, 95% CI: 1.049-1.091), smoking history (OR= 2.013, 95% CI: 1.268-3.195), and a decreased DBP (OR=0.980, 95% CI: 0.963-0.997) as independent risk factors for LEAD in DFU patients. A prolonged healing time was a prominent clinical feature of DFU complicated by LEAD. CONCLUSION: DFU patients have a high incidence of LEAD, which leads to high rates of disability and mortality and is associated with an advanced age, high smoking rate and longer healing time. A decreased DBP is also a risk factor for LEAD in DFU patients.

The incidences of adverse events in small-cell lung cancer patients after radiotherapy and immunotherapy treatment: a systematic review and meta-analysis.

Immunotherapy is important in treating small-cell lung cancer (SCLC), and its anti-tumor effects are better when combined with radiotherapy. However, the toxicity of this combination is little known. This study assessed the incidences of adverse events when adding radiotherapy to ICIs in patients with SCLC. We searched the online databases to identify eligible studies and included nine references. For extensive-stage SCLC patients, the median PFS ranged from 4.5 to 12.5 months, and median OS ranged from 8.4 to NR months, respectively. The incidences of grade 3 or higher pneumonitis, lung infection, diarrhea, and fatal adverse events were 8.7% (95% CI: 5%-14.7%), 6.7% (95% CI: 2.5%-16.5%), 12.6% (95% CI: 7.6%-20%), and 5.1% (95% CI: 2.1%-11.6%), respectively. Our findings suggest that radiotherapy plus ICIs may provide acceptable safety and favorable efficacy for SCLC patients.

Development and validation of a competency evaluation model for hospital infection prevention and control practitioners in the post-pandemic era: a mixed methods study.

BACKGROUND: During the coronavirus disease 2019 pandemic, the management of nosocomial infections became even more crucial. There is an urgent need to develop a competency model for healthcare practitioners to combat public health emergencies. AIM: To determine practitioners' competency in hospital infection prevention and control measures. METHODS: A theoretical framework was developed based on a literature review, key informant interviews, the Delphi method and a questionnaire survey. These items were evaluated based on response rate, maximum score, minimum score and mean score. Factor analyses, both exploratory and confirmatory, were used to determine the structure of the competency model. RESULTS: The effective response rate for the questionnaire was 88.29%, and Cronbach's α-coefficient was 0.964. Factor analysis revealed a Kaiser-Meyer-Olkin score of 0.945. Bartlett's test gave a χ2-value of 10523.439 (df=435; P<0.001). After exploratory factor analysis, the five-factor model was retained, four items were deleted and a five-dimensional, 26-item scale was obtained. The new structure's confirmatory factor analysis revealed high goodness of fit (comparative fit index=0.921; Tucker-Lewis index=0.911; standardized root mean square residual=0.053; root mean square error of approximation=0.044). CONCLUSION: The proposed scale is a useful tool to assess the competency of hospital infection prevention and control practitioners, which can help hospitals to improve infection prevention and control.

Novelty is not surprise: Human exploratory and adaptive behavior in sequential decision-making.

Classic reinforcement learning (RL) theories cannot explain human behavior in the absence of external reward or when the environment changes. Here, we employ a deep sequential decision-making paradigm with sparse reward and abrupt environmental changes. To explain the behavior of human participants in these environments, we show that RL theories need to include surprise and novelty, each with a distinct role. While novelty drives exploration before the first encounter of a reward, surprise increases the rate of learning of a world-model as well as of model-free action-values. Even though the world-model is available for model-based RL, we find that human decisions are dominated by model-free action choices. The world-model is only marginally used for planning, but it is important to detect surprising events. Our theory predicts human action choices with high probability and allows us to dissociate surprise, novelty, and reward in EEG signals.

A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies.

BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. METHODS: Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine triplet combination safety and efficacy. RESULTS: Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2  (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. CONCLUSIONS: The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.

MTMR2 promotes the progression of NK/T cell lymphoma by targeting JAK1.

OBJECTIVE: The aim of this study was to investigate the expression characteristics of MTMR2 in NK/T cell lymphoma (NKTCL), and to further study its relationship with clinical parameters and the prognosis of patients with NKTCL. In addition, the potential mechanisms of MTMR2 promoting the progression of NKTCL was further explored. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine MTMR2 level in peripheral blood of 45 patients with NK/T-cell lymphoma and 45 healthy volunteers. The interplay between MTMR2 expression and clinical indicators, as well as the prognosis of patients with NK/T-cell lymphoma was analyzed. Meanwhile, MTMR2 expression in NKTCL cell lines was verified by qRT-PCR. Subsequently, MTMR2 knockdown and the overexpression models were constructed using lentivirus in NKTCL cell lines, including SNK-6 and KHYG-1. Transwell invasion and cell wound healing assays were applied to analyze the effect of MTMR2 on the biological function of NKTCL cells. Finally, an in-depth study of the relationship between MTMR2 and JAK1 was conducted to explore the underlying mechanism. RESULTS: QRT-PCR results showed that the expression level of MTMR2 in the serum of patients with NKTCL was remarkably higher than that of healthy volunteers, and the difference was statistically significant (p<0.05). Compared with patients with low expression of MTMR2, patients with high expression of MTMR2 exhibited significantly higher incidence of distant metastasis and lower overall survival rate (p<0.05). The metastasis ability of NKTCL SNK-6 cells was remarkably attenuated in MTMR2 knockdown group when compared with the negative control sh-NC group (p<0.05). Meanwhile, the metastatic ability of NKTCL KHYG-1 cells in MTMR2 overexpressing group was remarkably enhanced when compared with the control NC group (p<0.05). The Luciferase reporter gene assay confirmed that MTMR2 could target JAK1, thereby jointly regulating the malignant progression of NKTCL. In addition, cell recovery experiment verified that JAK1 could partially reverse the enhanced metastatic ability of NKTCL cells induced by the overexpression of MTMR2. CONCLUSIONS: MTMR2 was highly expressed in NKTCL serum samples and cell lines, leading to high risk of distant metastasis and poor prognosis. In addition, MTMR2 might promote the malignant progression of NKTCL by regulating JAK1.

MiR-744 mediates the Oxaliplatin chemoresistance in colorectal cancer through inhibiting BIN1.

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide. However, lacking of novel and sensitive chemotherapy revealed the major challenge to improve the survival of CRC patients. The aim of this study was to explore the effect and mechanism of miR-744 on the oxaliplatin chemoresistance in CRC. Firstly, the levels of miR-744 were elevated significantly in CRC tissues from patients with oxaliplatin administration before surgery and in oxaliplatin-resistant HCT116 cells. Then, the oxaliplatin chemoresistance was enhanced by miR-744 overexpression, while was attenuated by miR-744 inhibition in HCT116 and T84 cells. Additionally, the level of BIN1 protein was found to be regulated negatively by miR-744, and BIN1 overexpression blocked the oxaliplatin chemoresistance induced by miR-744. Furthermore, BIN1 was proved to be a direct target of miR-744 by luciferase reporter assay. Taken together, these findings demonstrated that miR-744 might positively mediate the oxaliplatin chemoresistance through suppressing BIN1 expression in CRC cells, thus suggested a rationale target for the developing more effective strategies to reverse oxaliplatin resistance in CRC treatment.

One-shot learning and behavioral eligibility traces in sequential decision making.

In many daily tasks, we make multiple decisions before reaching a goal. In order to learn such sequences of decisions, a mechanism to link earlier actions to later reward is necessary. Reinforcement learning (RL) theory suggests two classes of algorithms solving this credit assignment problem: In classic temporal-difference learning, earlier actions receive reward information only after multiple repetitions of the task, whereas models with eligibility traces reinforce entire sequences of actions from a single experience (one-shot). Here, we show one-shot learning of sequences. We developed a novel paradigm to directly observe which actions and states along a multi-step sequence are reinforced after a single reward. By focusing our analysis on those states for which RL with and without eligibility trace make qualitatively distinct predictions, we find direct behavioral (choice probability) and physiological (pupil dilation) signatures of reinforcement learning with eligibility trace across multiple sensory modalities.

Cryptoanalysis on optical image encryption systems based on the vector decomposition technique in the Fourier domain.

In this paper, the security of optical cryptosystems based on the vector decomposition technique in the Fourier domain is analyzed. Compared to the conventional cryptosystem based on the equal modulus decomposition (EMD) technique, an additional EMD structure is introduced in the cascaded EMD-based cryptosystem; hence, the mask including the phase information of the Fourier spectrum is further encoded in the second EMD structure to enhance the security level. However, it is shown that the number of the private keys has not been increased in the cascaded EMD-based cryptosystem, which makes it possible to crack the cascaded EMD-based cryptosystem. Therefore, a chosen-plaintext attack (CPA) and a special attack with an arbitrarily given private key are proposed to retrieve information from encoded images obtained by the cascaded EMD-based cryptosystem. In addition, the security of the cryptosystem based on the random modulus decomposition (RMD) technique is also analyzed. Compared to the EMD-based cryptosystem in which the Fourier spectrum is decomposed into two vectors with equal moduli, the security level of the cryptosystem has been improved by using the RMD technique to decompose the spectrum into vectors with unequal moduli to decrease the number of the amplitude constraints. However, it is found that the arbitrarily given ciphertext provides the attackers enough information to retrieve the precise information of the plaintext without any knowledge of the private keys. A special attack is proposed to crack the RMD-based cryptosystem. This is the first time to report that these two cryptosystems based on the vector decomposition technique are attacked successfully. Numerical simulation is conducted to validate the feasibility and effectiveness of the proposed attacks.

Security analysis and enhancement of a cryptosystem based on phase truncation and a designed amplitude modulator.

In this paper, the security of a cryptosystem based on phase truncation and a designed amplitude modulator (AM) is evaluated. In the cryptosystem, an undercover AM used as an additional key is added to modulate the amplitude information of the spectrum in the Fourier plane. Compared to the conventional phase-truncated Fourier transform (PTFT)-based cryptosystem, the security of the cryptosystem is improved by increasing the number of unknown keys. However, it is found that the designed AM is irrelative to the plaintext, and one of the parameters in the designed AM contributes less to the security enhancement of the cryptosystem due to low key sensitivity. Based on the analysis, a special attack containing two iterative processes is proposed to crack the cryptosystem, in which the known-plaintext-attack-based iterative process I with a specific normalization operator is used to retrieve the designed AM and the amplitude-phase-retrieval-technique-based iterative process II is used to retrieve the corresponding plaintext from the arbitrarily given ciphertext with the help of the retrieved AM. In addition, an inherent drawback widely existing in PTFT-based cryptosystems is reported for the first time: most information of the original image could be retrieved using two correct phase keys (or only the first phase key) generated in the encryption process, even without the corresponding ciphertext in PTFT-based cryptosystems. To address this issue, a security-enhanced cryptosystem is proposed in this paper. Numerical simulation is carried out to demonstrate the effectiveness and feasibility of the proposed attack and cryptosystem.

Hybrid attack on an optical cryptosystem based on phase-truncated Fourier transforms and a random amplitude mask.

In this paper, the security of a cryptosystem based on phase-truncated Fourier transforms (PTFTs) and a random amplitude mask (RAM) is evaluated. In the cryptosystem, fake keys used as encryption keys in the second PTFT-based structure are generated by the first PTFT-based structure in which the RAM is encoded by random phase masks (RPMs) used as public keys. Compared to the classical PTFT-based encryption scheme, the security level of the cryptosystem is improved by using cascaded PTFTs to encode the encryption keys and the plaintext simultaneously. However, it is found that a known plaintext-ciphertext pair can provide enough constraints in the iterative process to retrieve the fake keys, which then can be used to retrieve unknown arbitrary plaintext from the corresponding ciphertext. Based on the analysis, we propose a specific attack based on hybrid iterative processes to break the cryptosystem. Two iterative processes with different constraints are involved in the proposed attack. The first known-plaintext-attack (KPA)-based iterative process is used to retrieve two fake keys with the help of two public keys and a known plaintext-ciphertext pair, while the second amplitude-phase retrieval algorithm-based iterative process with a median filter is employed to retrieve the plaintext from the corresponding ciphertext using two retrieval fake keys. To the best of our knowledge, it is the first time that the cryptosystem is attacked by the KPA-based iterative algorithm successfully. Numerical simulation results validate the feasibility and effectiveness of the proposed attack.

Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage.

AIM: Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage. PATIENTS AND METHODS: Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California). Other independent genome-wide mRNA expression profiles of articular cartilage from three patients with OA and three healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Integrative pathway enrichment analysis of DNA methylation and mRNA expression profiles was performed using integrated analysis of cross-platform microarray and pathway software. Gene ontology (GO) analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). RESULTS: We identified 1265 differentially methylated genes, of which 145 are associated with significant changes in gene expression, such as DLX5, NCOR2 and AXIN2 (all p-values of both DNA methylation and mRNA expression < 0.05). Pathway enrichment analysis identified 26 OA-associated pathways, such as mitogen-activated protein kinase (MAPK) signalling pathway (p = 6.25 × 10-4), phosphatidylinositol (PI) signalling system (p = 4.38 × 10-3), hypoxia-inducible factor 1 (HIF-1) signalling pathway (p = 8.63 × 10-3 pantothenate and coenzyme A (CoA) biosynthesis (p = 0.017), ErbB signalling pathway (p = 0.024), inositol phosphate (IP) metabolism (p = 0.025), and calcium signalling pathway (p = 0.032). CONCLUSION: We identified a group of genes and biological pathwayswhich were significantly different in both DNA methylation and mRNA expression profiles between patients with OA and controls. These results may provide new clues for clarifying the mechanisms involved in the development of OA.Cite this article: A. He, Y. Ning, Y. Wen, Y. Cai, K. Xu, Y. Cai, J. Han, L. Liu, Y. Du, X. Liang, P. Li, Q. Fan, J. Hao, X. Wang, X. Guo, T. Ma, F. Zhang. Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage. Bone Joint Res 2018;7:343-350. DOI: 10.1302/2046-3758.75.BJR-2017-0284.R1.

A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects. METHODS: A single-arm, open-label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m2 /d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28-day cycle. Another 5 patients with mismatch repair-deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m2 /d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression levels. RESULTS: The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression-free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors. CONCLUSIONS: In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m2 /d, and it was clinically active. PARP inhibitor-based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337-46. © 2018 American Cancer Society.

Security analysis of a double-image encryption technique based on an asymmetric algorithm.

In this paper, we evaluate the security of a double-image encryption technique based on an asymmetric algorithm. Compared with traditional cryptosystems based on a phase-truncated Fourier transform, the technique is able to improve the security of the encryption by combining a joint transform correlator; consequently, the encryption scheme is immune to some common attacks. We propose a special attack based on a phase retrieval algorithm with median filtering and normalization operation to break the cryptosystem. Low key sensitivity of a position parameter set has been found and an additional constraint is utilized to improve the attack to simplify the process and further decrease the computational time. Numerical simulation results show that the cryptosystem is vulnerable to the proposed special attack.

Simplified paraboloid phase model-based phase tracker for demodulation of a single complex fringe.

A regularized phase tracker (RPT) is an effective method for demodulation of single closed-fringe patterns. However, lengthy calculation time, specially designed scanning strategy, and sign-ambiguity problems caused by noise and saddle points reduce its effectiveness, especially for demodulating large and complex fringe patterns. In this paper, a simplified paraboloid phase model-based regularized phase tracker (SPRPT) is proposed. In SPRPT, first and second phase derivatives are pre-determined by the density-direction-combined method and discrete higher-order demodulation algorithm, respectively. Hence, cost function is effectively simplified to reduce the computation time significantly. Moreover, pre-determined phase derivatives improve the robustness of the demodulation of closed, complex fringe patterns. Thus, no specifically designed scanning strategy is needed; nevertheless, it is robust against the sign-ambiguity problem. The paraboloid phase model also assures better accuracy and robustness against noise. Both the simulated and experimental fringe patterns (obtained using electronic speckle pattern interferometry) are used to validate the proposed method, and a comparison of the proposed method with existing RPT methods is carried out. The simulation results show that the proposed method has achieved the highest accuracy with less computational time. The experimental result proves the robustness and the accuracy of the proposed method for demodulation of noisy fringe patterns and its feasibility for static and dynamic applications.