Identification of the molecular subtypes and signatures to predict the prognosis, biological functions, and therapeutic response based on the anoikis-related genes in colorectal cancer.

BACKGROUND: Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear. METHODS: We obtained transcriptomic profiles of CRC and 27 ARGs from The Cancer Genome Atlas, the Gene Expression Omnibus, and MSigDB databases, respectively. CRC tissue samples were classified into two clusters based on the expression pattern of ARGs, and their functional differences were explored. Hub genes were screened using weighted gene co-expression network analysis, univariate analysis, and least absolute selection and shrinkage operator analysis, and validated in cell lines, tissues, or the Human Protein Atlas database. We constructed an ARG-risk model and nomogram to predict prognosis in patients with CRC, which was validated using an external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, and drug sensitivity, between high- and low-risk groups were examined. RESULTS: Patients with CRC were divided into C1 and C2 clusters. Cluster C1 exhibited higher TME scores, whereas cluster C2 had favorable outcomes and a higher stemness index. Eight upregulated hub ARGs (TIMP1, P3H1, SPP1, HAMP, IFI30, ADAM8, ITGAX, and APOC1) were utilized to construct the risk model. The qRT-PCR, Western blotting, and immunohistochemistry results were consistent with those of the bioinformatics analysis. Patients with high risk exhibited worse overall survival (p < 0.01), increased stemness, TME, immune checkpoint expression, immune infiltration, tumor mutation burden, and drug susceptibility compared with the patients with low risk. CONCLUSION: Our results offer a novel CRC stratification based on ARGs and a risk-scoring system that could predict the prognosis, stemness, TME, immunophenotypes, and drug susceptibility of patients with CRC, thereby improving their prognosis. This stratification may facilitate personalized therapies.

CRISPR/Cas9: a powerful tool in colorectal cancer research.

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide and seriously threatens human health. The clustered regulatory interspaced short palindromic repeat/CRISPR-associate nuclease 9 (CRISPR/Cas9) system is an adaptive immune system of bacteria or archaea. Since its introduction, research into various aspects of treatment approaches for CRC has been accelerated, including investigation of the oncogenes, tumor suppressor genes (TSGs), drug resistance genes, target genes, mouse model construction, and especially in genome-wide library screening. Furthermore, the CRISPR/Cas9 system can be utilized for gene therapy for CRC, specifically involving in the molecular targeted drug delivery or targeted knockout in vivo. In this review, we elucidate the mechanism of the CRISPR/Cas9 system and its comprehensive applications in CRC. Additionally, we discussed the issue of off-target effects associated with CRISPR/Cas9, which serves to restrict its practical application. Future research on CRC should in-depth and systematically utilize the CRISPR/Cas9 system thereby achieving clinical practice.

A multicenter randomized phase II trial of hyperthermia combined with TPF induction chemotherapy compared with TPF induction chemotherapy in locally advanced resectable oral squamous cell carcinoma.

BACKGROUND: Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. METHODS: A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. RESULTS: A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. CONCLUSIONS: Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.

Suppressing Grating Lobes for Transcranial Focused Ultrasound System by Frequency-Modulated Excitation.

Transcranial focused ultrasound is a novel noninvasive therapeutic modality for glioblastoma and other disorders of the brain. However, because the phase aberrations caused by the skull need to be corrected with computed tomography (CT) images, the transcranial transducer is tightly fixed on the patient's head to avoid any variation in the relative position, and the focus shifting relies mainly on the capacity for electronic beam steering. Due to the presence of grating lobes and the rapid degradation of the focus quality with increasing focus-shifting distance, transcranial focus-shifting sonication may damage healthy brain tissue unintentionally. To reduce the risks associated with transcranial focused ultrasound therapy, linear frequency-modulated (FM) excitation is proposed. The k-space corrected pseudospectral time domain (PSTD) and acoustic holography approach based on the Rayleigh integral are combined to calculate the distribution of the deposited acoustic power. The corresponding simulation was performed with axial/lateral focus shifting at different distances. The distributions of the deposited acoustic power show that linear FM excitation can effectively suppress undesired prefocal grating lobes without compromising focus quality.

Design of a Versatile Angle-Rotatable Skull-Shaped Conformal Transcranial Focused Ultrasound Transducer for Noninvasive Brain Therapy.

Phase-controlled focused ultrasound transducers have opened up a new way to noninvasively treat brain diseases. However, due to the geometry and the heterogeneous medium of the human skull, the currently used hemispherical transducers cannot guarantee that the ultrasound emitted by the transducer penetrates the skull normally; consequently, the impact of the shear wave on the treatment area has to be considered. The usual approach is to turn off elements in the transducer with excessively large incident angles, but this approach reduces the efficiency of the transducer. This article presents the design of a novel transducer that can be rotated according to the different geometric shapes of the skull. The incident angles of the elements in the transducer are modified so that the effect of the shear wave on the treatment area can be ignored and the efficiency of the transducer is improved. The results of computed tomography (CT) model simulation of nine skulls verify the versatility and feasibility of the new transducer. We believe that this kind of rotatable transducer has clinical and engineering significance.

An efficient and accurate parallel hybrid acoustic signal correction method for transcranial ultrasound.

Phased-control focused ultrasound transducers provide a new and noninvasive treatment method for brain disease. However, improving the accuracy of phase correction and reducing the calculation time during treatment have always been contradictory constraints. In this paper, a hybrid acoustic signal correction (HASC) method combined with k-Wave stage and holography stage was introduced for phase correction and simulation of transcranial focused ultrasound. The k-Wave stage is mainly used to calculate the sound field in a heterogeneous medium (skull), which divides the sound field calculation process into paths that can be calculated in parallel, and the transcranial correction phase can also be obtained during the calculation. The holography stage is sufficient to simulate the acoustic field in the homogenous intracranial medium after ultrasound transmitting through the skull. The agreement of the k-space corrected pseudospectral time domain method and HASC method was assessed by statistical methods: linear regression between the two methods provided a slope of 0.9735, intercept of 0.0078, and R 2 of 0.9982. The Bland-Altman method provided a bias of 0.0015 and 95% limits of agreement 0.065 apart. We demonstrated that the difference in sound intensity at the focal point corrected by HASC and time reversal phase correction method was 0.2% and 0.5% in the results of simulation and experiment, respectively. Not only that, the phase calculation time by the HASC phase correction method can be reduced to 11 min on a multi GPU array, which has clinical potential for ultrasound treatment of brain therapy.

Evaluating Targeting Accuracy in the Focal Plane for an Ultrasound-guided High-intensity Focused Ultrasound Phased-array System.

Phased arrays are increasingly used as high-intensity focused ultrasound (HIFU) transducers in the existing extracorporeal ultrasound-guided HIFU (USgHIFU) systems. The HIFU transducers in such systems are usually spherical in shape with a central hole where a US imaging probe is mounted and can be rotated. The image on the plane of treatment can be reconstructed through the image sequence acquired during the rotation of the probe. Therefore, the treatment plan can be made on the reconstructed images. In order to evaluate the targeting accuracy in the focal plane of such systems, the protocol of a method using a bovine muscle and marker-embedded phantom is described. In the phantom, four solid balls at the corners of a square resin model serve as the reference markers in the reconstructed image. The target should be moved so that both its center and the center of the square model can coincide according to their relative positions in the reconstructed image. Swine muscle with a thickness of about 30 mm is placed above the phantom to mimic the beam path in clinical settings. After sonication, the treatment plane in the phantom is scanned and the boundary of the associated lesion is extracted from the scanned image. The targeting accuracy can be evaluated by measuring the distance between the centers of target and lesion, as well as three derivative parameters. This method cannot only evaluate the targeting accuracy of the target consisting of multiple focal spots rather than a single focal spot in a clinically relevant beam path of the USgHIFU phased-array system, but it can be also used in the preclinical evaluation or regular maintenance of USgHIFU systems configured with phased-array or self-focused HIFU transducer.

Feasibility of an electromagnetic compatibility method for MRgFUS using a wire mesh screen.

This study evaluated an electromagnetic compatibility method for high-intensity focused ultrasound (HIFU) and magnetic resonance (MR) imaging in an MR-guided focused ultrasound surgery using a conductive wire mesh screen. This screen has a good ultrasound transmission and shielding effectiveness. A hybrid acoustic simulation method was developed to analyze the effects of mesh parameters and the HIFU working frequency on the acoustic field. Experiments were performed to measure both acoustic pressure profile and radiated electromagnetic noise. With the proposed mesh screen, the electromagnetic radiation emission was reduced by 14dB at 128MHz while the acoustic focal intensity was reduced by less than 11% using one screen. This shielding method is easy to implement and requires no additional phase correction method. This method also improves the quality of MR images.

A radiation emission shielding method for high intensity focus ultrasound probes.

Electromagnetic compatibility (EMC) is a key issue in the design and development of safe and effective medical instruments. The treatment probes of high intensity focused ultrasound (HIFU) systems not only receive and transmit electromagnetic waves, but also radiate ultrasound waves, resulting in electromagnetic coupling. In this paper, an electromagnetic shielding method involving the enclosure of the probe in a copper wire mesh was introduced. First, sound pressure distribution simulations and measurements were performed using a hydrophone in order to evaluate the effects of the wire mesh on the acoustic performance of the HIFU system. The results indicated that the wire mesh did not disturb the normalized sound pressure field. In addition, the attenuation of the maximum pressure in the focal plane was equal to 6.2%. Then, the electronic emission level was tested in a chamber. After the implementation of the wire mesh, the 10-100 MHz frequency band radiation was suppressed, and the HIFU system satisfied the national EMC standards.

Multiple instance learning for computer aided detection and diagnosis of gastric cancer with dual-energy CT imaging.

Multiple instance learning algorithms have been increasingly utilized in computer aided detection and diagnosis field. In this study, we propose a novel multiple instance learning method for the identification of tumor invasion depth of gastric cancer with dual-energy CT imaging. In the proposed scheme, two level features, bag-level features and instance-level features are extracted for subsequent processing and classification work. For instance-level features, there is some ambiguity in assigning labels to selected patches. An improved Citation-KNN method is presented to solve this problem. Compared with benchmarking state-of-the-art multiple instance learning algorithms using the same clinical dataset, the proposed algorithm can achieve improved results. The experimental evaluation is performed using leave-one-out cross validation with the total accuracy of 0.7692. The proposed multiple instance learning algorithm serves as an alternative method for computer aided diagnosis and identification of tumor invasion depth of gastric cancer with dual-energy CT imaging techniques.

An estimation of mechanical stress on alveolar walls during repetitive alveolar reopening and closure.

Alveolar overdistension and mechanical stresses generated by repetitive opening and closing of small airways and alveoli have been widely recognized as two primary mechanistic factors that may contribute to the development of ventilator-induced lung injury. A long-duration exposure of alveolar epithelial cells to even small, shear stresses could lead to the changes in cytoskeleton and the production of inflammatory mediators. In this paper, we have made an attempt to estimate in situ the magnitudes of mechanical stresses exerted on the alveolar walls during repetitive alveolar reopening by using a tape-peeling model of McEwan and Taylor (35). To this end, we first speculate the possible ranges of capillary number (Ca) ≡ µU/γ (a dimensionless combination of surface tension γ, fluid viscosity µ, and alveolar opening velocity U) during in vivo alveolar opening. Subsequent calculations show that increasing respiratory rate or inflation rate serves to increase the values of mechanical stresses. For a normal lung, the predicted maximum shear stresses are <15 dyn/cm(2) at all respiratory rates, whereas for a lung with elevated surface tension or viscosity, the maximum shear stress will notably increase, even at a slow respiratory rate. Similarly, the increased pressure gradients in the case of elevated surface or viscosity may lead to a pressure drop >300 dyn/cm(2) across a cell, possibly inducing epithelial hydraulic cracks. In addition, we have conceived of a geometrical model of alveolar opening to make a prediction of the positive end-expiratory pressure (PEEP) required to splint open a collapsed alveolus, which as shown by our results, covers a wide range of pressures, from several centimeters to dozens of centimeters of water, strongly depending on the underlying pulmonary conditions. The establishment of adequate regional ventilation-to-perfusion ratios may prevent recruited alveoli from reabsorption atelectasis and accordingly, reduce the required levels of PEEP. The present study and several recent animal experiments likewise suggest that a lung-protective ventilation strategy should not only include small tidal volume and plateau pressure limitations but also consider such cofactors as ventilation frequency and inflation rate.

The efficacy and hyperthermic release of doxorubicin from liposomal doxorubicin hydrochloride in rabbit VX2 tumours.

PURPOSE: To establish optimum conditions for anti-tumour therapy, we evaluated the efficacy of doxorubicin using liposomal doxorubicin and local hyperthermia to improve the anti-tumour efficacy over liposomal doxorubicin alone in rabbit VX2 tumours. MATERIALS AND METHODS: A VX2 tumour model was established in New Zealand white rabbits, which were randomly divided into five groups: 1) control, 2) free doxorubicin hydrochloride (Dox), 3) liposomal doxorubicin hydrochloride (L-Dox), 4) L-Dox plus 41 °C thermotherapy (L-Dox + 41 °C TT); and 5) L-Dox plus 43 °C thermotherapy (L-Dox + 43 °C TT). To achieve complete tumour remission, multiple high-dose administrations (5 mg/kg, once per week for a total of 3 weeks) were given. An ultrasound hyperthermia instrument was used to induce local hyperthermia and the systemic toxicity of Dox was evaluated by changes in weight, blood count and serum lactic dehydrogenase. The anti-tumour effect of Dox was evaluated by observing the gross tumour volume, weight and rabbit survival. RESULTS: The white blood cell count following administration of Dox or L-Dox was lower than for control animals and those treated with L-Dox + 41 °C TT. There was no difference between the groups with regard to the red blood cell count. Compared with the control and Dox groups, tumour proliferation was significantly inhibited following administration of L-Dox, L-Dox + 41 °C TT and L-Dox + 43 °C TT, as evidenced by the difference in tumour volume, weight and survival time. Differences in tumour proliferation were also found between the L-Dox and thermotherapy groups. CONCLUSION: Local hyperthermia combined with L-Dox can significantly improve anti-tumour efficacy and reduce systemic toxicity.

A micromechanical model for estimating alveolar wall strain in mechanically ventilated edematous lungs.

To elucidate the micromechanics of pulmonary edema has been a significant medical concern, which is beneficial to better guide ventilator settings in clinical practice. In this paper, we present an adjoining two-alveoli model to quantitatively estimate strain and stress of alveolar walls in mechanically ventilated edematous lungs. The model takes into account the geometry of the alveolus, the effect of surface tension, the length-tension properties of parenchyma tissue, and the change in thickness of the alveolar wall. On the one hand, our model supports experimental findings (Perlman CE, Lederer DJ, Bhattacharya J. Am J Respir Cell Mol Biol 44: 34-39, 2011) that the presence of a liquid-filled alveolus protrudes into the neighboring air-filled alveolus with the shared septal strain amounting to a maximum value of 1.374 (corresponding to the maximum stress of 5.12 kPa) even at functional residual capacity; on the other hand, it further shows that the pattern of alveolar expansion appears heterogeneous or homogeneous, strongly depending on differences in air-liquid interface tension on alveolar segments. The proposed model is a preliminary step toward picturing a global topographical distribution of stress and strain on the scale of the lung as a whole to prevent ventilator-induced lung injury.

Ultrasound and computed tomography features of primary acinic cell carcinoma in the parotid gland: a retrospective study.

OBJECTIVE: The aim of this study was to characterize the ultrasound (US) and computed tomography (CT) findings of primary acinic cell carcinoma (AciCC) of the parotid gland. SUBJECTS AND METHODS: Seventy patients (70 lesions) with histopathologically proven AciCC underwent US or CT examination. The following characteristics were assessed on US images: size, shape, border, echogenicity, echotexture, internal structure, distal acoustic enhancement, and vascularity. The following characteristics were evaluated on CT images: size, shape, border, density, CT values on plain and contrast-enhanced scans, enhancement pattern, enhancement degree, and surrounding bone destruction. RESULTS: On US images, lesions were irregular, well-defined, hypoechoic, heterogeneous, and poorly vascularized. On CT images, lesions were regular and well-defined, and showed slight heterogeneous enhancement. CONCLUSION: These findings suggest that most primary AciCCs show benign features on US and CT.

[A positioning method of ultrasound probe in MR system].

This paper provides a method of positioning the ultrasound probe in MR system. Machining 6 slots or cylinder perpendicular to the ultrasound probe surface on the edge of ultrasound probe as markers, 12 central cylinder ends are chosen as positioning points. By calculating these positioning points' coordinates in MR's coordinate system, the coordinate transformation between the ultrasound and MR coordinate system can be computed. Furthermore, by taking advantage of redundant information, calculating errors can be reduced and the precision can be improved.

Quantitative assessment of acoustic intensity in the focused ultrasound field using hydrophone and infrared imaging.

With the popularity of ultrasound therapy in clinics, characterization of the acoustic field is important not only to the tolerability and efficiency of ablation, but also for treatment planning. A quantitative method was introduced to assess the intensity distribution of a focused ultrasound beam using a hydrophone and an infrared camera with no prior knowledge of the acoustic and thermal parameters of the absorber or the configuration of the array elements. This method was evaluated in both theoretical simulations and experimental measurements. A three-layer model was developed to calculate the acoustic field in the absorber, the absorbed acoustic energy during the sonication and the consequent temperature elevation. Experiments were carried out to measure the acoustic pressure with the hydrophone and the temperature elevation with the infrared camera. The percentage differences between the derived results and the simulation are <4.1% for on-axis intensity and <21.1% for -6-dB beam width at heating times up to 360 ms in the focal region of three phased-array ultrasound transducers using two different absorbers. The proposed method is an easy, quick and reliable approach to calibrating focused ultrasound transducers with satisfactory accuracy.

Transcostal high-intensity focused ultrasound treatment using phased array with geometric correction.

In the high-intensity focused ultrasound treatment of liver tumors, ultrasound propagation is affected by the rib cage. Because of the diffraction and absorption of the bone, the sound distribution at the focal plane is altered, and more importantly, overheating on the rib surface might occur. To overcome these problems, a geometric correction method is applied to turn off the elements blocked by the ribs. The potential of steering the focus of the phased-array along the propagation direction to improve the transcostal treatment was investigated by simulations and experiments using different rib models and transducers. The ultrasound propagation through the ribs was computed by a hybrid method including the Rayleigh-Sommerfeld integral, k-space method, and angular spectrum method. A modified correction method was proposed to adjust the output of elements based on their relative area in the projected "shadow" of the ribs. The simulation results showed that an increase in the specific absorption rate gain up to 300% was obtained by varying the focal length although the optimal value varied in each situation. Therefore, acoustic simulation is required for each clinical case to determine a satisfactory treatment plan.

[Framework design of MRI guided phased HIFU system and software development].

This paper introduced a new structure of MRI guided P-HIFU therapy system and software implementation based on the current P-HIFU system and interface provided by MRI vendor. The tests showed that the system's software can achieve the appropriate form of treatment need.

Effects of different parameters in the fast scanning method for HIFU treatment.

PURPOSE: High-intensity focused ultrasound is a promising method for the noninvasive treatment of benign and malignant tumors. This study analyzes the effects of scanning path, applied power, and geometric characteristics of the transducer on ablation using fast scanning method, a new scanning method that uses high-intensity focused ultrasound at different blood perfusion levels. METHODS: Two transducers, six scanning paths, and three focal patterns were used to examine the ablation results of the fast scanning method using power densities from 1.35 × 10(7) W∕m(3) to 4.5 × 10(7) W∕m(3) and blood perfusion rates from 2 × 10(-3) ml∕ml∕s to 16 × 10(-3) ml∕ml∕s. The Pennes equation was solved using the finite-difference time-domain method to simulate the heating procedure. RESULTS: Based on the results of the fast-scanning method, the different scanning paths exhibited small effect on the total treatment time supported by both simulation and least-square fit. Similar-sized lesions can result from the five different repeated paths, whereas a random path may lead to relative large fluctuations in ablation volume because of asymmetry of the lesions. Higher power levels increase the lesion volume and decrease the treatment time required for ablating a target area using the fast scanning method, whereas increased blood perfusion has the opposite effect on ablation volume and treatment time. A symmetric lesion can be produced through fast scanning method using a 65-element and a 90-element transducer. However, lesion production using the same operation scheme differs between the two transducers. CONCLUSIONS: Unlike traditional scanning methods, fast scanning method produces a planned lesion regardless of scanning path, as long as the path consists of repeated subsequences. This attribute makes fast scanning method an easy-operation scheme that produces relatively large symmetric lesions in homogeneous tissues. Applied power is the most important factor; however, high blood perfusion levels can limit or even hinder the full ablation of the target area. Therefore, tissue perfusion and transducer type should be given special attention to ensure the success and safety of ablation treatment.

Ultrasonographic appearances of mucoepidermoid carcinoma of the salivary glands.

OBJECTIVE: The objective of this study was to investigate the ability of sonography for diagnosis of mucoepidermoid carcinoma (MEC) in the salivary glands. STUDY DESIGN: Sonographic images of 74 cases were analyzed retrospectively; the features evaluated included size, echogenicity, shape, internal structure, distal acoustic enhancement, and regional lymph node enlargement and vascularization, and categorized them into 3 groups based on histology (low, intermediate, and high grade). RESULTS: The lesion size of low-grade MEC was smaller than those of intermediate- and high-grade MEC. MEC lesions of the salivary glands were mostly associated with heterogeneous echotexture, indistinct margins, irregular shape, and absence of distal acoustic enhancement. They sometimes showed cystic areas, calcifications, regional lymph node enlargement, or were well vascularized on Doppler. There were no significant sonographic differences in low-, intermediate-, and high-grade MEC. CONCLUSIONS: Salivary MEC presents a variety of sonographic appearances, which would aid in the diagnosis of salivary MEC.