Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

Long-Distance Coherent Propagation of High-Velocity Antiferromagnetic Spin Waves.

We report on coherent propagation of antiferromagnetic (AFM) spin waves over a long distance (∼10 µm) at room temperature in a canted AFM α-Fe_{2}O_{3} owing to the Dzyaloshinskii-Moriya interaction (DMI). Unprecedented high group velocities (up to 22.5 km/s) are characterized by microwave transmission using all-electrical spin wave spectroscopy. We derive analytically AFM spin-wave dispersion in the presence of the DMI which accounts for our experimental results. The AFM spin waves excited by nanometric coplanar waveguides have large wave vectors in the exchange regime and follow a quasilinear dispersion relation. Fitting of experimental data with our theoretical model yields an AFM exchange stiffness length of 1.7 Å. Our results provide key insights on AFM spin dynamics and demonstrate high-speed functionality for AFM magnonics.

Erratum: Long-Distance Coherent Propagation of High-Velocity Antiferromagnetic Spin Waves [Phys. Rev. Lett. 130, 096701 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.096701.

Nonlocal Detection of Interlayer Three-Magnon Coupling.

A leading nonlinear effect in magnonics is the interaction that splits a high-frequency magnon into two low-frequency magnons with conserved linear momentum. Here, we report experimental observation of nonlocal three-magnon scattering between spatially separated magnetic systems, viz. a CoFeB nanowire and a yttrium iron garnet (YIG) thin film. Above a certain threshold power of an applied microwave field, a CoFeB Kittel magnon splits into a pair of counterpropagating YIG magnons that induce voltage signals in Pt electrodes on each side, in excellent agreement with model calculations based on the interlayer dipolar interaction. The excited YIG magnon pairs reside mainly in the first excited (n=1) perpendicular standing spin-wave mode. With increasing power, the n=1 magnons successively scatter into nodeless (n=0) magnons through a four-magnon process. Our results demonstrate nonlocal detection of two separately propagating magnons emerging from one common source that may enable quantum entanglement between distant magnons for quantum information applications.

Erratum: Chiral Spin-Wave Velocities Induced by All-Garnet Interfacial Dzyaloshinskii-Moriya Interaction in Ultrathin Yttrium Iron Garnet Films [Phys. Rev. Lett. 124, 027203 (2020)].

This corrects the article DOI: 10.1103/PhysRevLett.124.027203.

Protective Role of lncRNA TTN-AS1 in Sepsis-Induced Myocardial Injury Via miR-29a/E2F2 Axis.

OBJECTIVE: Approximately 50% of patients with sepsis encounter myocardial injury. The mortality of septic patients with cardiac dysfunction (approx. 70%) is much higher than that of patients with sepsis only (20%). A large number of studies have suggested that lncRNA TTN-AS1 promotes cell proliferation in a variety of diseases. This study delves into the function and mechanism of TTN-AS1 in sepsis-induced myocardial injury in vitro and in vivo. METHODS: LPS was used to induce sepsis in rats and H9c2 cells. Cardiac function of rats was assessed by an ultrasound system. Myocardial injury was revealed by hematoxylin-eosin (H&E) staining. Gain and loss of function of TTN-AS1, miR-29a, and E2F2 was achieved in H9c2 cells before LPS treatment. The expression levels of inflammatory cytokines and cTnT were monitored by ELISA. The expression levels of cardiac enzymes as well as reactive oxygen species (ROS) activity and mitochondrial membrane potential (MMP) were measured using the colorimetric method. The expression levels of TTN-AS1, miR-29a, E2F2, and apoptosis-related proteins were measured by RT-qPCR and/or western blotting. The proliferation and apoptosis of H9c2 cells were separately detected by CCK-8 and flow cytometry. Luciferase reporter assay was used to verify the targeting relationships among TTN-AS1, miR-29a and E2F2, and RIP assay was further used to confirm the binding between miR-29a and E2F2. RESULTS: TTN-AS1 was lowly expressed, while miR-29a was overexpressed in the cell and animal models of sepsis. Overexpression of TTN-AS1 or silencing of miR-29a reduced the expression levels of CK, CK-MB, LDH, TNF-B, IL-1B, and IL-6 in the supernatant of LPS-induced H9c2 cells, attenuated mitochondrial ROS activity, and enhanced MMP. Consistent results were observed in septic rats injected with OE-TTN-AS1. Knockdown of TTN-AS1 or overexpression of miR-29a increased LPS-induced inflammation and injury in H9c2 cells. TTN-AS1 regulated the expression of E2F2 by targeting miR-29a. Overexpression of miR-29a or inhibition of E2F2 abrogated the suppressive effect of TTN-AS1 overexpression on myocardial injury. CONCLUSION: This study indicates TTN-AS1 attenuates sepsis-induced myocardial injury by regulating the miR-29a/E2F2 axis and sheds light on lncRNA-based treatment of sepsis-induced cardiomyopathy.

The joint action of unfolded protein response, circZc3h4, and circRNA Scar in procymidone-induced testicular injury in adolescent mice.

Procymidone (PCM) is a low toxicity fungicide, and an endocrine-disrupting chemical (EDC) that particularly damages the reproductive system of male vertebrates. In present study, adolescent mice in control, low-, medium-, and high-dose groups were orally administered 0 (equal volume of soybean oil), 50, 100, and 200 mg/kg/day PCM, respectively, for 21 days. Additionally, a three-dimensional culture of mouse testes was performed in vitro, and the control, low dose (0.33 × 10-5  M), medium dose (1 × 10-5  M), and high dose (3 × 10-5  M) PCM groups were established. We have found that, under both in vivo and in vitro conditions, all doses of PCM caused damage to mouse testes. Moreover, the levels of circZc3h4 RNA and Zc3h4 decreased while miR-212 increased in all treatment groups, with a corresponding rise in circRNA Scar and fall in Atp5b, compared to those in the control group, and all the changes showed a dose-response relationship. Besides, we have identified that low doses of PCM could activate the Ire1-Xbp1 pathway, whereas the medium and high doses activated the Perk-Elf2α-Atf4, Ire1-Xbp1, and Atf6 pathways. And it is, therefore, speculated that the unfolded protein response (UPR), circZc3h4 and circRNA Scar may have taken joint action in testicular injury in adolescent mice induced by PCM at the no observed adverse effect level (NOAEL, 100 mg/kg/day) and below NOAEL doses.

Reconfigurable Spin-Wave Interferometer at the Nanoscale.

Spin waves can transfer information free of electron transport and are promising for wave-based computing technologies with low-power consumption as a solution to severe energy losses in modern electronics. Logic circuits based on the spin-wave interference have been proposed for more than a decade, while it has yet been realized at the nanoscale. Here, we demonstrate the interference of spin waves with wavelengths down to 50 nm in a low-damping magnetic insulator. The constructive and destructive interference of spin waves is detected in the frequency domain using propagating spin-wave spectroscopy, which is further confirmed by the Brillouin light scattering. The interference pattern is found to be highly sensitive to the distance between two magnetic nanowires acting as spin-wave emitters. By controlling the magnetic configurations, one can switch the spin-wave interferometer on and off. Our demonstrations are thus key to the realization of spin-wave computing system based on nonvolatile nanomagnets.

Strain-Driven Dzyaloshinskii-Moriya Interaction for Room-Temperature Magnetic Skyrmions.

Dzyaloshinskii-Moriya interaction in magnets, which is usually derived from inversion symmetry breaking at interfaces or in noncentrosymmetric crystals, plays a vital role in chiral spintronics. Here we report that an emergent Dzyaloshinskii-Moriya interaction can be achieved in a centrosymmetric material, La_{0.67}Sr_{0.33}MnO_{3}, by a graded strain. This strain-driven Dzyaloshinskii-Moriya interaction not only exhibits distinctive two coexisting nonreciprocities of spin-wave propagation in one system, but also brings about a robust room-temperature magnetic skyrmion lattice as well as a spiral lattice at zero magnetic field. Our results demonstrate the feasibility of investigating chiral spintronics in a large category of centrosymmetric magnetic materials.

Flutamide induces uterus and ovary damage in the mouse via apoptosis and excessive autophagy of cells following triggering of the unfolded protein response.

Intrauterine exposure to flutamide not only causes abnormal development of the reproductive organs in male offspring, but also damages ovaries and uteri. The unfolded protein response (UPR) is believed to play an important role in embryo development and teratogenic processes. In the present study, pregnant mice were administered either flutamide (300mg kg-1 day-1, p.o.) on an equivalent volume of soybean oil (control) on Days 12-18 of gestation. Eight weeks after birth, female offspring in the flutamide-treated group had a lower bodyweight and lower ovarian and uterine weights, but there was no significant difference in uterine and ovarian weights normalised by bodyweight between the flutamide-treated and control groups. Furthermore, histopathological changes were observed in all uteri and ovaries in the flutamide-treated group, with fewer and less-developed follicles in the ovaries. In both the uteri and ovaries, flutamide increased the expression of UPR members, although the expression of cell cycle-related genes remained unchanged compared with the control group. Flutamide increased the expression of all autophagy- and apoptosis-related genes evaluated in the uterus, as well as some in the ovary. The results suggest that the in utero exposure of mice to flutamide may contribute to uterine and ovarian damage in the offspring, with endoplasmic reticulum stress possibly triggered by the UPR leading to the induction of excessive autophagy and apoptosis.

Advances in the application of mesenchymal stem cells, exosomes, biomimetic materials, and 3D printing in osteoporosis treatment.

Owing to an increase in the aging population, osteoporosis has become a severe public health concern, with a high prevalence among the elderly and postmenopausal adults. Osteoporosis-related fracture is a major cause of morbidity and mortality in elderly and postmenopausal adults, posing a considerable socioeconomic burden. However, existing treatments can only slow down the process of osteoporosis, reduce the risk of fractures, and repair fractures locally. Therefore, emerging methods for treating osteoporosis, such as mesenchymal stem cell transplantation, exosome-driving drug delivery systems, biomimetic materials, and 3D printing technology, have received increasing research attention, with significant progress. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can differentiate into different types of functional cells. Exosomes play a key role in regulating cell microenvironments through paracrine mechanisms. Bionic materials and 3D printed scaffolds are beneficial for the reconstruction and repair of osteoporotic bones and osteoporosis-related fractures. Stem cells, exosomes, and biomimetic materials represent emerging technologies for osteoporosis treatment. This review summarizes the latest developments in these three aspects.

An in-silico method with graph-based multi-label learning for large-scale prediction of circRNA-disease associations.

Circular RNAs (circRNAs) have been proved to be implicated in various pathological processes and play vital roles in tumors. Increasing evidence has shown that circRNAs can serve as an important class of regulators, which have great potential to become a new type of biomarkers for tumor diagnosis and treatment. However, their biological functions remain largely unknown, and it is costly and tremendously laborious to investigate the molecular mechanisms of circRNAs in human diseases based on conventional wet-lab experiments. The emergence and rapid growth of genomics data sources has provided new opportunities for us to decipher the underlying relationships between circRNAs and diseases by computational models. Therefore, it is appealing to develop powerful computational models to discover potential disease-associated circRNAs. Here, we develop an in-silico method with graph-based multi-label learning for large-scale of prediction potential circRNA-disease associations and discovery of those most promising disease circRNAs. By fully exploiting different characteristics of circRNA space and disease space and maintaining the data local geometric structures, the graph regularization and mixed-norm constraint terms are also incorporated into the model to help to make prediction. Results and case studies show that the proposed method outperforms other models and could effectively infer potential associations with high accuracy.

Spin Wave Injection and Propagation in a Magnetic Nanochannel from a Vortex Core.

Spin waves can be used as information carriers with low energy dissipation. The excitation and propagation of spin waves along reconfigurable magnonic circuits is the subject of much interest in the field of magnonic applications. Here we experimentally demonstrate an effective excitation of spin waves in reconfigurable magnetic textures at frequencies as high as 15 GHz and wavelengths as short as 80 nm from Ni80Fe20 (Py) nanodisk-film hybrid structures. Most importantly, we demonstrate these spin wave modes, which were previously confined within a nanodisk, can now couple to and propagate along a nanochannel formed by magnetic domain walls at zero magnetic bias field. The tunable high-frequency, short-wavelength, and propagating spin waves may play a vital role in energy efficient and programmable magnonic devices at the nanoscale.

The Preventive Effects of Lactobacillus casei on Acute Lung Injury Induced by Lipopolysaccharide.

Lactobacillus has been reported to inhibit acute lung injury (ALI). However, the molecular mechanism of Lactobacillus casei (L. casei) in preventing ALI has not been identified, so we investigated whether L. casei pretreatment could inhibit the activation of TLR4/MyD88/NF-κB signaling pathway following ALI. ALI model was established by intraperitoneal injection of 2 mg/kg lipopolysaccharide (LPS) to female BALB/c mice. In L. casei LC2W group, mice were intragastrically administrated L. casei LC2W for a week, before the ALI modeling. The serum of normal BALB/c mice after intragastric administration of L. casei LC2W was used for in vitro cell assays. The serum was pre-incubated with mouse macrophage cell line (RAW264.7) and human lung cell line (HLF-A), then LPS was added to co-incubate. Compared with ALI model group, L. casei LC2W pretreatment significantly reduced lung pathological damage, the number of neutrophils and total cells in bronchoalveolar lavage fluid. Besides, L. casei LC2W pretreatment could significantly reverse the abnormal expression of ICAM-1, IL-6, TNF-α and IL-10 in lung tissue and serum, plus, L. casei LC2W significantly reduced the phosphorylation levels of IRAK-1 and NF-κB p65. In vitro, the serum decreased the up-regulation of IL-6 and TNF-α in cell lines induced by LPS. In conclusion, L. casei LC2W intragastric administration pretreatment could significantly improve LPS-induced ALI in mice, probably through circulation to reach the lungs so as to inhibit the inflammatory response induced by activation of TLR4/MyD88/NF-κB signaling pathway.

Chiral Spin-Wave Velocities Induced by All-Garnet Interfacial Dzyaloshinskii-Moriya Interaction in Ultrathin Yttrium Iron Garnet Films.

Spin waves can probe the Dzyaloshinskii-Moriya interaction (DMI), which gives rise to topological spin textures, such as skyrmions. However, the DMI has not yet been reported in yttrium iron garnet (YIG) with arguably the lowest damping for spin waves. In this work, we experimentally evidence the interfacial DMI in a 7-nm-thick YIG film by measuring the nonreciprocal spin-wave propagation in terms of frequency, amplitude, and most importantly group velocities using all electrical spin-wave spectroscopy. The velocities of propagating spin waves show chirality among three vectors, i.e., the film normal direction, applied field, and spin-wave wave vector. By measuring the asymmetric group velocities, we extract a DMI constant of 16 µJ/m^{2}, which we independently confirm by Brillouin light scattering. Thickness-dependent measurements reveal that the DMI originates from the oxide interface between the YIG and garnet substrate. The interfacial DMI discovered in the ultrathin YIG films is of key importance for functional chiral magnonics as ultralow spin-wave damping can be achieved.

Bone mineral density measurement combined with vertebral fracture assessment increases diagnosis of osteoporosis in postmenopausal women.

OBJECTIVE: Osteoporosis is diagnosed based on the results of BMD assessment and/or fragility fractures. Vertebral fracture is the most common fragility fracture. Many vertebral fractures are asymptomatic and are not clinically recognized. Early detection of vertebral fracture may increase diagnosis of osteoporosis. In this study, we performed BMD measurement combined with vertebral fracture assessment (VFA) by DXA for the postmenopausal women receiving the first bone densitometry and studied the impact of VFA on the diagnosis of osteoporosis. METHODS: A total of 502 postmenopausal women were enrolled in our study. Patients' age was 66.7 ± 9.5 years. All patients had BMD assessment and VFA by dual-energy X-ray absorptiometry. Genant's semiquantitative assessment was used. The impact of VFA on the diagnosis of osteoporosis was studied. All parameters of groups were compared using the Chi-squared test. RESULTS: There were 257 patients with T-score ≤-2.5, 202 patients with a T-score between -1 and - 2.5, and 43 patients with BMD within the normal range. There were 162 patients with 345 fractured vertebrae identified by VFA, among which 84% of patients were previously unknown. Osteoporosis or severe osteoporosis was presented in 51.2% patients diagnosed by BMD alone, in 55.2% patients diagnosed by BMD plus fracture history, and in 62.4% of patients diagnosed by BMD plus fracture history and VFA. Severe osteoporosis significantly increased by 17.2% in patients receiving VFA. CONCLUSIONS: VFA combined with BMD can detect previously unknown vertebral fractures and increase clinical diagnosis of osteoporosis. It is plausible to speculate that this method should be considered in postmenopausal women for the first BMD assessment.

Circular RNA circ_001350 regulates glioma cell proliferation, apoptosis, and metastatic properties by acting as a miRNA sponge.

Glioma is an aggressive malignancy with increasing incidence and threatens people's health worldwide. Accumulating evidence revealed that circular RNAs (circRNAs) play important functions in cancers. A previous study demonstrated that circ_001350 was elevated in glioma tissue samples than nontumorous tissue specimens screened by high-throughput microarray. The level of circ_001350 in glioma tissue specimens and cell lines was detected by quantitative real-time polymerase chain reaction. The Fisher exact test was carried out to estimate the correlation of circ_001350 level with clinical characteristics. Cell proliferation, apoptosis, and motility abilities were detected using cell counting kit-8, clonogenic, flow cytometry, and transwell experiments, respectively. The potential target of circ_001350 was identified by the luciferase assay. circ_001350 level was significantly enhanced in glioma tissue specimens and cells. Further, elevated expression of circ_001350 was closely linked to patients' clinical severity. Knockdown of circ_001350 could inhibit cell proliferation and metastatic properties and increase apoptotic cells. circ_001350 could directly bind to miR-1236 and regulate its expression to exert oncogenic functions. Collectively, circ_001350 directly sponges miR-1236, thus contributing to malignant progression of glioma.

Repression of let-7b-5p prevents the development of multifidus muscle dysfunction by promoting vitamin D accumulation via upregulation of electron transfer flavoprotein alpha subunit in a rat model of multifidus muscle injury.

Multifidus muscle dysfunction is associated with the multifidus muscle injury (MMI), which ultimately result in the low-back pain. Increasing evidence shows that microRNAs (miRs) may be involved in multifidus muscle dysfunction. In this study, we tested the hypothesis that downregulation of let-7b-5p may inhibit the multifidus muscle dysfunction development and progression. The target prediction program and luciferase activity determination confirmed electron transfer flavoprotein alpha subunit (ETFA) as a direct target gene of let-7b-5p. To study the mechanisms and functions of let-7b-5p in relation to ETFA in MMI progression, we prepared rats with experimental MMI, and a lentivirus-based packaging system was designed to upregulate expressions of let-7b-5p, and downregulate the expression of ETFA. ETFA was identified as a target gene of let-7b-5p. Older age, a longer duration of pain, and higher visual analog scale and Oswestry disability index scores for the patients with chronic low-back pain were linked to a more severe degree of degenerative muscle atrophy and fatty infiltration. Increased expression of let-7b-5p and decreased expression of ETFA and vitamin D receptor (VDR) were positively correlated with multifidus muscle dysfunction. Downregulated let-7b-5p could inhibit infiltration of collagen fibers, reverse the ultrastructural changes of multifidus muscle, and induce the VDR expression, thereby repair the MMI. The results provided a potential basis for let-7b-5p that could support targeted intervention in multifidus muscle dysfunction. Collectively, this study confirmed that downregulation of let-7b-5p has a potential inhibitory effect on the development of the function of the musculus myocytes by upregulating ETFA.

Influence of bone densitometry on the anti-osteoporosis treatment after fragility hip fracture.

BACKGROUND: Fragility fracture significantly increases risk of future fracture. The fragility fracture cycle should be disrupted. The secondary fracture prevention is important for the patients with fragility hip fracture. The pharmacotherapy for osteoporosis is important for prevention of new fracture. However, many patients with hip fracture do not receive osteoporosis treatment. This retrospective study investigates the influence of bone mineral density (BMD) assessment on the initiation of anti-osteoporosis medications in the hospitalized patients with fragility hip fracture. METHODS: This retrospective research enrolled 1211 patients with fragility hip fracture 50 years of age and older. Among 1211 patients aged from 50 to 103 years with the average age of 77.83 ± 9.95 years, there were 807 females and 404 males. There were 634 fractures of femoral neck and 577 intertrochanteric fractures of femur. We examined whether patients had received bone mineral density assessment and received anti-osteoporosis therapy during the period of hospitalization. The patients were divided into BMD assessment group and no BMD assessment group. Measurement data were expressed as mean ± standard deviation and compared with t test. All parameters of groups were compared with Chi-square test. RESULTS: Of 1211 patients, 331 (27.33%) had received BMD assessment and 925 (76.38%) had received anti-osteoporosis drugs during the period of hospitalization. The rate of bisphosphonate use was lower and only 11.31% in the total patients. The anti-osteoporosis treatment rate was 93.66% in the patients receiving BMD assessment and 69.89% in the patients without BMD assessment (p < 0.01). The zoledronate use significantly increased from 6.7% in the patients without BMD assessment to 23.56% in the patients receiving BMD assessment (p < 0.01). CONCLUSIONS: BMD assessment is a good basis for communication between patients and orthopedic surgeons. BMD assessment significantly increases the initiation of osteoporosis treatment and bisphosphonate use in the patients with hip fracture during the period of hospitalization.

LncRNA DLX6-AS1/miR-129-5p/DLK1 axis aggravates stemness of osteosarcoma through Wnt signaling.

Osteosarcoma is the most common primary bone tumor and occurs most frequently in adolescents. Cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy, and can drive cancer recurrence. In this study, we aimed to investigate the effect of Long noncoding RNAs (lncRNAs) DLX6-AS1 on osteosarcoma stemness and the underlying mechanism involved. DLX6-AS1 enhanced osteosarcoma stemness in vitro and in vivo. Moreover, DLX6-AS1 competitively interacted with miR-129-5p to DLK1, resulting in activation of Wnt signaling and promotion of stemness in osteosarcoma. DLX6-AS1 functionally interplayed with miR-129-5p to form a reciprocal feedback loop to activate Wnt signaling. High DLX6-AS1 expression was observed in osteosarcoma tissues, and predicted a poor prognosis for osteosarcoma patients. Our study suggests that DLX6-AS1, combined with miR-129-5p and DLK1, can be utilized as factors for the clinical diagnosis and prognosis of osteosarcoma, and may be potential targets for the treatment of osteosarcoma.