Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Wool keratin as a novel alternative protein: A comprehensive review of extraction, purification, nutrition, safety, and food applications.

The growing global population and lifestyle changes have increased the demand for specialized diets that require protein and other essential nutrients for humans. Recent technological advances have enabled the use of food bioresources treated as waste as additional sources of alternative proteins. Sheep wool is an inexpensive and readily available bioresource containing 95%-98% protein, making it an outstanding potential source of protein for food and biotechnological applications. The strong structure of wool and its indigestibility are the main hurdles to achieving its potential as an edible protein. Although various methods have been investigated for the hydrolysis of wool into keratin, only a few of these, such as sulfitolysis, oxidation, and enzymatic processes, have the potential to generate edible keratin. In vitro and in vivo cytotoxicity studies reported no cytotoxicity effects of extracted keratin, suggesting its potential for use as a high-value protein ingredient that supports normal body functions. Keratin has a high cysteine content that can support healthy epithelia, glutathione synthesis, antioxidant functions, and skeletal muscle functions. With the recent spike in new keratin extraction methods, extensive long-term investigations that examine prolonged exposure of keratin generated from these techniques in animal and human subjects are required to ascertain its safety. Food applications of wool could improve the ecological footprint of sheep farming and unlock the potential of a sustainable protein source that meets demands for ethical production of animal protein.

Immune Checkpoint Inhibitor-Induced Primary Hyperparathyroidism in a Small-Cell Lung Cancer Patient: A Case Report.

Immunotherapy is increasingly being used in the treatment of tumors. Adverse effects, however, are not uncommon, with the most common immune-related adverse events (IrAEs) including rash, fatigue, anemia, diarrhea, constipation, and elevated transaminase, among others. Rare IrAEs, which may include thrombocytopenia, hypoparathyroidism, pancreatitis glomerulonephritis, Guillain-Barré syndrome, and celiac disease, may also present. Immune checkpoint inhibitor (ICI)-induced primary hyperparathyroidism (PHPT) has not yet been reported on, and no research currently exists regarding its pathogenesis. We describe how a 50-year-old man diagnosed with advanced small-cell lung cancer (SCLC) developed severe PHPT after receiving the programmed cell death (PD)-1 inhibitor camrelizumab. The patient eventually died of respiratory failure and a progressive malignancy. We speculate that the hypercalcemia and hypophosphatemia observed in this case were secondary to ICI-induced PHPT. Although fatal PHPT is rare, early intervention may reduce the risk of future complications. Therefore, further exploration of the underlying mechanisms is needed to guide solutions.

The short-term safety and effectiveness of a new distal perforating stent graft in Type B aortic dissection: a retrospective study.

BACKGROUND: Spinal artery ischemia (SCI) events can result from over coverage of the descending thoracic aorta with a coated stent during Thoracic Endovascular Aortic Repair (TEVAR). The aim of this study was to determine whether a new distal perforating stent could reduce the incidence of spinal cord ischemia while remodeling the true lumen. METHODS: TBAD patients treated with Talos stent in the vascular surgery Department of Yan 'an Hospital affiliated to Kunming Medical University between December 2017 and October 2019 were retrospectively analyzed to investigate the short-term safety and effectiveness of Talos stent. RESULTS: A total of the 20 patients, including 14 males and 6 females, with an average age of 52.65 ± 8.98 years (range 37-68 years), were included in the analysis. Stent-grafts were successfully implanted in all patients under local anesthesia, with a technical success rate of 100%. The average operation time was 50.75 ± 13.01 min. A total of 2 cases (10%) presented chest pain associated with intercostal artery ischemia that was relieved on the 3rd and 5th postoperative day, respectively. Postoperative mean follow-up was 16.15 ± 3.99 months. No paraplegia or other complications occurred. And stenting did not induce new tears. No migration, deformation, or fracture of the stents occurred. There was a significant difference in the remolding of the true lumen preoperatively and at 12 months postoperatively (P < 0.05). CONCLUSIONS: Talos stent has achieved satisfactory clinical treatment results in short term.

Alternating Hemiplegia of Childhood Caused by ATP1A3 Mutations: A Report of Two Cases.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder. Most cases are reported as sporadic disorder due to de novo variants, and few with family members involved. Two boys were hospitalized due to epileptic seizures occurred initially at age of six to seven months. During the course of the disease, there were repeated episodes of paroxysmal weakness or paralysis affecting one side of the body. Genetic testing showed that both patients carried heterozygous missense mutations in theATP1A3 gene (OMIM: 614820): c.3025 (exon 22) A>G (p.K1009E) and c.2443 (exon 18) G>A (p.E815K). Flunarizine can significantly improve the paroxysmal motor symptoms of pediatric patients with alternating hemiplegia.

Immunohistochemical analysis of adipokine and adipokine receptor expression in the breast tumor microenvironment: associations of lower leptin receptor expression with estrogen receptor-negative status and triple-negative subtype.

BACKGROUND: The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). METHODS: We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. RESULTS: Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P < 0.0001) in the overall sample and among Black women only. LEP, ADIPOQ, ADIPOR1, and ADIPOR2 IHC expression were not significantly associated with breast tumor clinicopathology. CONCLUSIONS: Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.

Structural, Photophysical, and Electrochemical Properties of Doubly Fused Porphyrins and Related Fused Chlorins.

The electrochemical and physicochemical properties of tetraphenylporphyrins and tetraphenylchlorins with two fused indanedione (IND) or malononitrile (MN) groups and two antipodal Br, Ph, or H ß-substituents are investigated in nonaqueous media. These compounds were synthesized by oxidative fusion of free-base trans-chlorins, followed by metalation. The corresponding free-base di-fused chlorins were also isolated as intermediates and characterized for comparisons. The examined di-fused porphyrins (DFP) and di-fused chlorins (DFC) are represented as MDFP(Y)2(R)2 and H2DFC(Y)2(R)2, where M = 2H, CuII, NiII, ZnII, and CoII, Y is a fused indanedione (IND) or malononitrile group (MN), and R = H, Br, or Ph. The IND- and MN-appended compounds in both series exhibit the expected two one-electron oxidations but quite different redox behavior is observed upon reduction, where the free-base IND-appended chlorins show four reversible one-electron reductions, compared to only two for the related free-base MN-appended chlorins. Although porphyrin trianions and tetraanions have been recently described for derivatives with highly electron-withdrawing and/or π-extending substituents, this seems not to be the case for the doubly fused IND-chlorins, where the first two one-electron additions are proposed to be located at the conjugated macrocycle and the last two at the fused IND groups, each of which is reduced at a different potential, consistent with the behavior expected for two equivalent and interacting redox centers. Unlike the examined chlorins, which are all stable in their electroreduced forms, the electrogenerated anionic forms of the di-fused porphyrins are all highly reactive and characterized by cyclic voltammograms having reduction peaks not only for the synthesized compounds added to solution but also for one or more new redox active species formed at the electrode surface in homogeneous chemical reactions following electron transfer. Comparisons are made between electrochemical behavior of the structurally related porphyrins and chlorins and the sites of electron transfer assigned on the basis of known electrochemical diagnostic criteria. One of the compounds, ZnDFP(MN)2, was also structurally characterized as having a ruffled and twisted macrocyclic conformation.

Synthesis, Electrochemistry, and Reversible Interconversion among Perhalogenated Hydroxyphenyl Ni(II) Porphyrins, Porphodimethenes, and Porpho-5,15-bis-paraquinone Methide.

Two octahalogenated nickel(II) hydroxyphenylporphyrins were synthesized and characterized as to their electrochemical and spectroscopic properties as well as their reactivity in neutral, acidic, and basic nonaqueous media. The newly synthesized complexes are represented as NiPorCl8 and NiPorBr8, where Por is the dianion of meso-tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin. The UV-vis spectra of NiPorCl8 and NiPorBr8 vary with the solvent and degree of axial coordination but are almost identical to each other in a given solvent. These spectra are also substantially different from that of the unhalogenated NiPor parent porphyrin (which resembles nickel tetraphenylporphyrin, NiTPP), and they also differ from the spectra of ß-octahalogenated NiTPPCl8 and NiTPPBr8 under the same solution conditions. The NiPorX8 spectra are stable with time and interpreted in terms of 4- or 6-coordinate derivatives in 13 different nonaqueous solvents. This is not the case, however, in DMF or DMSO, where a transient six-coordinate complex is initially formed upon dissolving the NiPorCl8, followed by the formation of an air-oxidized porphodimethene-like product called porpho-5,15-bis-paraquinone methide, with the time of this chemical transformation depending upon the concentration of the porphyrin in solution. The initial species formed from NiPorCl8 and NiPorBr8 after the first one-electron addition in CH2Cl2 is stable for short times at -60 °C, but this is not the case at room temperature, where a rapid homogeneous chemical reaction occurs. Four additional redox reactions are also observed in CH2Cl2, and the UV-visible spectra of several in-situ-generated electroreduction products are compared with that of chemically synthesized porphodimethenes formed in neutral, acidic, and basic solutions of CH2Cl2 containing acid in the form of TFA or base in the form of TBA+X, where X = OAc-, CN-, and OH-. Finally, a reversible electrochemically driven conversion between the Ni(II) hydroxyphenylporphyrin and a reduced porphodimethene or oxidized porphyrin-like product, porpho-5,15-bis-paraquinone methide, is described.

Tetra-2,3-pyrazinoporphyrazines with Peripherally Appended Pyridine Rings. 20. Mono- and Pentanuclear AlIII and GaIII Complexes: Synthesis and Physicochemical and Photoactivity Studies.

The autocyclotetramerization of the precursor 2,3-dicyano-5,6-di(2'-pyridyl)pyrazine [(CN)2Py2Pyz] in the presence of MCl3 compounds (M = AlIII, GaIII) leads to the formation of the new mononuclear porphyrazine complexes [Py8TPyzPzMCl]·xH2O (Py8TPyzPz = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion). From these species, the hydroxide analogues [Py8TPyzPzMOH]·xH2O were obtained by contact with hot water, and their corresponding pentanuclear species [(PdCl2)4Py8TPyzPzMCl]·xH2O could be easily formed by the reaction with PdCl2. Physicochemical characterization of the mono- and pentanuclear macrocycles was based on elemental analysis, and mass, powder X-ray, and IR spectra. UV-vis spectral studies of the mononuclear species in solutions of DMF, DMSO, or pyridine (c ≈ 10-5-10-6 M) indicate (mainly in DMF and DMSO) the initial presence of aggregation, in some cases accompanied by the concomitant occurrence for the complex of a one-electron reduction. While disaggregation into a single species evolves spontaneously over time, the -1 charged species, eventually also found present, can be brought back to its neutral form by addition of a slight amount of HCl, the final spectrum showing the presence of the starting neutral species in its pure monomeric form. Similar aspects were faced also for the parent pentanuclear complexes. Cyclic voltammetry experiments, conducted for the mono-/pentanuclear complexes in DMF and DMSO (c ≈ 10-4 M), exhibit progressive one-electron reductions (1 → 4) characterized by E1/2 values (V vs SCE) positioned to significantly less negative values than those known for the phthalocyanine (Pc) analogues, these data confirming the previously already proven higher electron-deficient character of the MII derivatives of the Py8TPyzPz macrocycle with respect to Pc. The role of the present new series of AlIII and GaIII macrocyclic species to act as photosensitizers for the generation of singlet oxygen, 1O2, the cytotoxic agent in the anticancer treatment known as photodynamic therapy (PDT), has been explored in DMF/HCl. Among the quantum yields ΦΔ, the value found for the GaIII complex [Py8TPyzPzGaCl] (0.68), practically coincident with that observed for the TTDPz analogue (0.69), is well above those of most porphyrazines analogues (ΦΔ = 0.4-0.6), a result encouraging further research work for potential applications in the biochemical field.

Spectral, Electrochemical, and ESR Characterization of Manganese Tetraarylporphyrins Containing Four ß,ß'-Pyrrole Fused Butano and Benzo Groups in Nonaqueous Media.

Two series of ß,ß'-pyrrole butano- and benzo-substituted mangenese(III) tetraarylporphyrins were synthesized and characterized with regard to their spectral and electrochemical properties. The investigated compounds have the general formula butano(Ar)4PorMnCl and benzo(Ar)4PorMnCl, where Por is the dianion of the porphyrin and Ar is a p-CH3Ph, Ph or p-ClPh group on each of the four meso-positions of the macrocycle. Each manganese(III) butano- or benzoporphyrin was examined in CH2Cl2 and/or pyridine containing 0.1 M tetra- n-butylammonium perchlorate and the data then were compared to that of the parent tetraarylporphyrins having the same meso-substituents. Up to four reductions are observed for each compound, the first being metal-centered to generate a Mn(II) porphyrin, and the second and third being porphyrin ring-centered to give a Mn(II) porphyrin π-anion radical and dianion, respectively. The one-electron reduced manganese porphyrins have an ESR spectrum with signals at g⊥= 5.6-5.8 and g// = 2.0, indicating a mixture of the four- and five-coordinated Mn(II) complexes in a high-spin state (3d5, S = 5/2, I = 5/2). Data from cyclic voltammetry and spectroelectrochemistry both suggest that formation of the porphyrin dianion is followed by a chemical reaction at the electrode surface to give an electroactive phlorin anion. The effects of solvent and porphyrin substituents on ultraviolet-visible light (UV-vis) spectra, redox potentials, and electron transfer mechanisms are discussed.

Tetra-2,3-pyrazinoporphyrazines with Peripherally Appended Pyridine Rings. 19. Pentanuclear Octa(2-pyridyl)tetrapyrazinoporphyrazines Carrying Externally Carboranthiolate Groups: Physicochemical Properties and Potentialities as Anticancer Drugs.

New pentanuclear porphyrazine complexes of formula [{Pd(CBT)2}4LM]· xH2O (L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato anion, CBT = m-carborane-1-thiolate, and M = MgII(H2O), ZnII, PdII) were prepared in good yield as dark green hydrated amorphous solids by reaction of the respective pentanuclear species [(PdCl2)4LM] with m-carboran-1-thiol in CH3CN. Physicochemical characterization of the new species was carried out by elemental and thermogravimetric analysis along with IR and 1H/13C NMR measurements. UV-vis spectral characterization performed in DMSO, DMF, and pyridine solution provided information about the stability of the new homo/heteropentanuclear species and their tendency to undergo detachment of the peripheral Pd(CBT)2 groups. The data from NMR, UV-vis, and electrochemical experiments indicate that external coordination of the Pd(CBT)2 units to the mononuclear [LM] species affects only slightly the π electron distribution within the internal macrocyclic choromophore. The Pd(CBT)2 units are released in pyridine solution and in the case of the ZnII complex [{Pd(CBT)2}4LZn] give rise to a finely crystalline light-yellow solid identified by single-crystal X-ray work as the trans isomer of the bispyridine adduct [py2(CBT)2Pd]. The new pentanuclear macrocyclic complexes behave in DMF solution as active photosensitizers for singlet oxygen production, 1O2, the cytotoxic agent in anticancer photodynamic therapy, and have larger quantum yield values (ΦΔ = 0.6-0.7) than those found on average for the related tetrapyrazinoporphyrazine analogs (ΦΔ = 0.4-0.6). The presence of the CBT groups in the currently investigated complexes opens up the possibility for their use in boron neutron capture therapy, leading potentially to new bimodal anticancer curative drugs.

Synthesis and Electrochemical Characterization of Acetylacetone (acac) and Ethyl Acetate (EA) Appended ß-Trisubstituted Push-Pull Porphyrins: Formation of Electronically Communicating Porphyrin Dimers.

Two new families of "push-pull" tetraphenylporphyrins with one acetylacetone (acac) or ethyl acetate (EA) moiety at a ß-pyrrole position of the macrocycle and two Br or Ph substituents at the antipodal ß-positions were synthesized and structurally, spectroscopically, and electrochemically characterized. The examined porphyrins are represented as MTPP(R)2acac and MTPP(R)2EA (where R = Br or Ph and M = H2, Co, Ni, Cu, or Zn). NiTPP(Br)2acac exhibits an extremely nonplanar conformation (Δ24 = 0.44 Å, ΔCß = 0.82 Å), while H2TPP(Br)2EA and ZnTPP(Ph)2EA exhibit a quasi-planar conformation. All of the synthesized acac-appended porphyrins show a keto-enol tautomerism in solution, which results in formation of hydrogen bonded dimers as evidenced by 1H NMR and mass spectrometry. Dimers were also detected under the electrochemical conditions for the dibromo derivatives but not the diphenyl substituted porphyrins. A facile stepwise and reversible electrogeneration of the electronically communicating porphyrin dimers is observed for MTPP(Br)2acac where M = CuII, NiII, or ZnII.

Homoleptic Platinum Azo-iminate Complexes via Hydrogenative Cleavage of Formazans.

Homoleptic platinum azo-iminate complexes are formed when triarylformazans are treated with Pt(DMSO)2Cl2 under reducing conditions. The transformation represents a three-proton, three-electron reduction of each formazan and offers a new route for accessing this class of redox-active ligands. The reaction is general for triarylformazans with both electron-donating and electron-withdrawing substituents, and four complexes in total are described. X-ray crystal structures of all four complexes are presented and are consistent with an electronic structure consisting of a formal Pt(II) center, where each azo-iminate is in a monoanionic radical form and contributes five π electrons. The complexes are all diamagnetic, indicating delocalization of the π system over both ligands. The complexes are further characterized by cyclic voltammetry, which shows multiple ligand-centered redox events, including proton-coupled oxidation waves. UV-vis spectroelectrochemistry provides further insight into the nature of the redox events. UV-vis absorption spectroscopy shows strong visible absorption bands attributed to HOMO → LUMO transitions, which is corroborated by time-dependent DFT computations on representative examples.

Octakis(2-pyridyl)porphyrazine and Its Neutral Metal Derivatives: UV-Visible Spectral, Electrochemical, and Photoactivity Studies.

Tetrapyrrolic porphyrazine macrocycles with externally appended 2-pyridyl rings were synthesized and characterized as to their spectroscopic, electrochemical, and photophysical properties. The investigated compounds are represented as [Py8PzH2], the unmetalated octakis(2-pyridyl)porphyrazine, and the metal complexes [Py8PzM], where M is MgII(H2O), CuII, ZnII, or CoII. The spectroscopic properties and the electrochemical behavior of these compounds were examined in solution of polar (pyridine, dimethyl sulfoxide, and dimethylformamide) and nondonor solvents (CHCl3, CH2Cl2), and the data were compared with those obtained from earlier studies on the related tetrapyrazinoporphyrazines, [Py8TPyzPzM], and the tetraquinoxalinoporphyrazines, [Py8QxPzM], also bearing externally 2-pyridyl rings, and characterized by a more extended central π-conjugated macrocyclic framework. The newly synthesized porphyrazines possess good solubility and are present in their monomeric form in all the examined solvents as shown by UV-visible spectra. The unmetalated species and metal derivatives undergo multiple one-electron reductions within the potential range of the nonaqueous examined solvents. The derivatives with nonredox active metal centers could accept four electrons on the conjugated macrocycle, while the CoII complex was characterized by a single one-electron oxidation and five reductions in DMSO. The photosensitizer activity for the generation of singlet oxygen was also examined for the MgII(H2O) and ZnII complexes in DMF, with measured ΦΔ values being, respectively, 0.42 and 0.64, this latter value indicating the ZnII species as being a promising material for use as anticancer agent in photodynamic therapy.

Facile and Reversible Electrogeneration of Porphyrin Trianions and Tetraanions in Nonaqueous Media.

The first examples for the facile, reversible, and stepwise electrogeneration of triply ring-reduced porphyrin macrocycles are presented. The investigated compounds are represented as MTPP(NO2)(PE)6, MTTP(PE)8, NiTPP(NO2)(Ph)4, and MTPP(CN)4, where TTP and TPP are the dianions of tetratolylporphyrin and tetraphenylporphyrin, respectively, NO2, phenylethynyl (PE), and CN are substituents at the ß-pyrrole positions of the macrocycle, and M = CuII, NiII, ZnII, CoII, or 2H. Each porphyrin undergoes three or four reductions within the negative potential limit of the electrochemical solvent. The UV-visible spectra of the first three reduction products were characterized by means of thin-layer UV-vis spectroelectrochemistry, and the generation of multianionic porphyrins is interpreted in terms of extensive stabilization of the LUMOs due to the electron-withdrawing and/or extended π-conjugation of the ß-substituents.

FokI Polymorphism of the Vitamin D Receptor Gene Is Associated with Susceptibility to Gastric Cancer: A Case-Control Study.

Vitamin D is a potential protective agent against cancer, and its activity is mediated mainly by vitamin D receptor (VDR). The FokI polymorphism (rs10735810) represents a T-to-C transition (ATG to ACG) in exon 2 of the VDR gene, and this ATG represents the translation-initiation codon, encoded by the f allele. The FokI polymorphism results in the generation of a protein shortened by three amino acids, translated from the downstream ATG codon (the F allele). We investigated the relationship between the FokI polymorphism and gastric cancer in a Chinese Han population. A total of 187 patients and 212 healthy controls were enrolled. The FokI polymorphism was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. The f allele frequency was higher in patients than that in controls (51.6% and 43.6%, P < 0.05). Multivariate logistics regression analysis revealed patients with the f allele (Ff + ff) showed a higher risk of gastric cancer [odds ratio (95% confidence interval) 2.73 (1.13~4.32)]. Patients with the f allele (Ff + ff) also presented a poorly differentiated type of gastric cancer (P < 0.05) and higher levels of C-reactive protein on admission than the FF group (5.5 ± 2.4 mg/L vs. 3.4 ± 1.3 mg/L, P < 0.05). Here, we show an association between the VDR FokI polymorphism and the susceptibility to gastric cancer, which may be helpful for early detection of high-risk individuals with the f allele for gastric cancer. Conversely, the F allele may be a protective factor against gastric cancer.

Towards an Automated MEMS-based Characterization of Benign and Cancerous Breast Tissue using Bioimpedance Measurements.

Micro-Electro-Mechanical-Systems (MEMS) are desirable for use within medical diagnostics because of their capacity to manipulate and analyze biological materials at the microscale. Biosensors can be incorporated into portable lab-on-a-chip devices to quickly and reliably perform diagnostics procedure on laboratory and clinical samples. In this paper, electrical impedance-based measurements were used to distinguish between benign and cancerous breast tissues using microchips in a real-time and label-free manner. Two different microchips having inter-digited electrodes (10 µm width with 10 µm spacing and 10 µm width with 30 µm spacing) were used for measuring the impedance of breast tissues. The system employs Agilent E4980A precision impedance analyzer. The impedance magnitude and phase were collected over a frequency range of 100 Hz to 2 MHz. The benign group and cancer group showed clearly distinguishable impedance properties. At 200 kHz, the difference in impedance of benign and cancerous breast tissue was significantly higher (3110 Ω) in the case of microchips having 10 µm spacing compared to microchip having 30 µm spacing (568 Ω).

A Semi-Automated Positioning System for contact-mode Atomic Force Microscopy (AFM).

Contact mode Atomic Force Microscopy (CM-AFM) is popularly used by the biophysics community to study mechanical properties of cells cultured in petri dishes, or tissue sections fixed on microscope slides. While cells are fairly easy to locate, sampling in spatially heterogeneous tissue specimens is laborious and time-consuming at higher magnifications. Furthermore, tissue registration across multiple magnifications for AFM-based experiments is a challenging problem, suggesting the need to automate the process of AFM indentation on tissue. In this work, we have developed an image-guided micropositioning system to align the AFM probe and human breast-tissue cores in an automated manner across multiple magnifications. Our setup improves efficiency of the AFM indentation experiments considerably. Note to Practitioners: Human breast tissue is by nature heterogeneous, and in the samples we studied, epithelial tissue is formed by groups of functional breast epithelial cells that are surrounded by stromal tissue in a complex intertwined way. Therefore sampling a specific cell type on an unstained specimen is very difficult. To aid us, we use digital stained images of the same tissue annotated by a certified pathologist to identify the region of interest (ROI) at a coarse magnification and an image-guided positioning system to place the unstained tissue near the AFM probe tip. Using our setup, we could considerably reduce AFM operating time and we believe that our setup is a viable supplement to commercial AFM stages with limited X-Y range.

Molecular Mechanism of Vitamin D Receptor Modulating Wnt/ß-catenin Signaling Pathway in Gastric Cancer.

Background: Gastric cancer is the most common gastrointestinal cancer worldwide. The latest data showed that it was the fourth leading cause of cancer-related death. The unobvious symptom and the difficulties lying in the early diagnosis largely affect the effect of the treatment. Therefore, it becomes particularly important to investigate the related genes and signal transduction pathways in gastric cancer. Our previous study found that the vitamin D receptor (VDR) gene FokI polymorphism may be associated with susceptibility to gastric cancer in the Chinese Han population. However, the mechanism of VDR affecting gastric cancer is unknown. In this study, we explored the molecular mechanism and the possible signaling pathway of VDR modulating carcinogenesis and progression of gastric cancer. Methods: The expression of VDR in gastric cancer cell lines was interfered by plasmid transfection and RNA interference technology. And then we analyzed the cell viability and invasive ability by MTT assay, colony formation assay, and transwell migration assay, and detected the expression of VDR and several signaling proteins in gastric cancer cells by SDS-PAGE and Western blotting. Results: The overexpression of VDR can significantly inhibit the viability and invasive ability of gastric cancer cells; on the contrary, when VDR siRNA inhibits the expression of VDR, the viability and invasive ability of gastric cancer cells enhanced. VDR expression levels in gastric cancer cells treated with 1,25 (OH) 2D3 showed a time-dependent increased expression; and with the increase of the VDR expression, the expression of ß-catenin decreased gradually, but the expression of E-cadherin showed a time-dependent increase (P < 0.05). Compared with the mutant-type VDR gene(ff) cells, the degree of ß-catenin decline was significantly enhanced after transfected with homozygous wild-type VDR gene (FF) plasmids (p<0.05). Conclusions: The results of this study indicate that VDR FokI polymorphism plays an important role in the malignant phenotype of gastric cancer cells, such as proliferation, invasion, and clone formation. When the VDR is activated by its ligand, it can prevent the nuclear import of ß-catenin, affect the E-cadherin level, inhibit the proliferation of gastric cancer cells, which suggested that VDR FokI gene may play a role of cancer suppressor via Wnt/ß-catenin signaling pathway.

Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma.

Liver cancer is a common malignancy with high morbidity and mortality rates. Changes in liver metabolism are key factors in the development of primary hepatic carcinoma, and mitochondrial dysfunction is closely related to the occurrence and development of tumours. Accordingly, the study of the metabolic mechanism of mitochondria in primary hepatic carcinomas has gained increasing attention. A growing body of research suggests that defects in mitochondrial respiration are not generally responsible for aerobic glycolysis, nor are they typically selected during tumour evolution. Conversely, the dysfunction of mitochondrial oxidative phosphorylation (OXPHOS) may promote the proliferation, metastasis, and invasion of primary hepatic carcinoma. This review presents the current paradigm of the roles of aerobic glycolysis and OXPHOS in the occurrence and development of hepatocellular carcinoma (HCC). Mitochondrial OXPHOS and cytoplasmic glycolysis cooperate to maintain the energy balance in HCC cells. Our study provides evidence for the targeting of mitochondrial metabolism as a potential therapy for HCC.