Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma.

BACKGROUND: Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined. METHODS: We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5). RESULTS: We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with high MICA expression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+ NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cells ex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells. CONCLUSIONS: Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.

Scannable Dual-Focus Metalens with Hybrid Phase.

Metalenses with two foci in the longitudinal or transverse direction, called bifocal or dual-focus metalenses, are promising building blocks in tomography techniques, data storage, and optical tweezers. For practical applications, relative movement between the beam and specimen is required, and beam scanning is highly desirable for high-speed operation without vibration. However, dual-focus metalenses employ a hyperbolic phase that experiences off-axis aberrations, which is not suitable for beam scanning. Here, we demonstrated a scannable dual-focus metalens by employing a new phase called "hybrid phase". The hybrid phase consists of a hyperbolic phase inside and a quadratic phase outside to reduce off-axis aberrations while maintaining a high numerical aperture. We show that the two foci of the scannable dual-focus metalens move together without severe distortion for incident angles of up to 2.5°. Our design easily extends to the case of multifocusing, which is essential for various applications ranging from imaging to manipulation.

Periodontal disease and cancer risk: A nationwide population-based cohort study.

Background: Although emerging evidence suggests that periodontitis might increase the risk of cancer, comorbidity and lifestyle behaviors, such as smoking and body mass index (BMI), may have confounded this reported association. This study aimed to investigate whether chronic periodontitis is associated with cancer risk using a large, nationwide database. Methods: We conducted a population-based, retrospective cohort study using data from the Korean National Health Insurance Cohort Database obtained between January 2003 and December 2015. We included 713,201 individuals without a history of cancer who were followed up to 10 years. Confounding factors included demographic factors (age, sex, income, and residential area), lifestyle behaviors (smoking history and BMI), and comorbidities, such as hypertension, diabetes, heart failure, and pulmonary disease, using the Charlson Comorbidity Index. Multivariable Cox regression analysis was applied to estimate the adjusted hazard ratio (aHR) for cancer risk. Results: Of the 713,201 participants, 53,075 had periodontitis and were placed in the periodontitis group; the remaining 660,126 individuals were included as the control group. Overall, the cumulative incidence of cancer in the periodontitis group was 2.2 times higher than that in the control group. The periodontitis group had an increased risk of total cancer compared to the control group after adjusting for age, sex, comorbidities, BMI, and smoking history (aHR, 1.129; 95% confidence interval [CI], 1.089-1.171; P<0.0001). When examining specific cancer types, significant associations were also observed between periodontitis and stomach cancer (aHR, 1.136; 95% CI, 1.042-1.239; P=0.0037), colon cancer (aHR, 1.129; 95% CI, 1.029-1.239; P=0.0105), lung cancer (aHR, 1.127; 95% CI, 1.008-1.260; P=0.0353), bladder cancer (aHR, 1.307; 95% CI, 1.071-1.595; P=0.0085), thyroid cancer (aHR, 1.191; 95% CI, 1.085-1.308; P=0.0002), and leukemia (aHR, 1.394; 95% CI, 1.039-1.872; P=0.0270). There was no significant association between the development of secondary malignancy and periodontitis in cancer survivors who were alive 5 years after they were diagnosed with the primary malignancy. Conclusions: Periodontal disease, including periodontitis, was associated with increased risk of cancer, which persisted after controlling for confounding factors. Further prospective research is warranted to establish a causal relationship.

Nanoscale Focus Pinspot for High-Purity Quantum Emitters via Focused-Ion-Beam-Induced Luminescence Quenching.

Epitaxially grown quantum dots (QDs), especially embedded in photonic structures, play an essential role in various quantum photonic systems as on-demand single-photon sources. However, these QDs often suffer from adjacent unwanted emitters, which contribute to the background noise of the QD emission and fundamentally limit the single-photon purity. In this paper, a nanoscale focus pinspot (NFP) technique using focused-ion-beam-induced luminescence quenching enables us to improve single-photon purity from site-controlled QD as a proof-of-concept experiment. The optical quality of the QD emission is not degraded while the signal-to-noise ratio of the QD is improved. Moreover, the QD after the NFP technique reveals the single-photon nature at further elevated temperatures owing to the reduced background noise. As the NFP technique is nondestructive, it retains the apparent physical structures and photonic functions, thereby indicating its promising potential for applying diverse high-purity quantum emitters, particularly integrated in photonic devices and circuits.

Bone Density After Teriparatide Discontinuation With or Without Antiresorptive Therapy in Pregnancy- and Lactation-Associated Osteoporosis.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare and severe disorder that causes low-trauma or spontaneous fractures, most commonly multiple vertebral fractures, in the late pregnancy or lactation period [1]. In severe PLO, teriparatide (TPTD) might aid in bone mineral density (BMD) recovery and subsequent fracture risk reduction. However, it is unclear whether TPTD can be discontinued without sequential antiresorptive therapy (ART) in premenopausal women with PLO. In this retrospective cohort study, we investigated the changes in BMD in premenopausal women with PLO treated with TPTD 20 mcg daily with or without sequential ART. Data for 67 patients diagnosed with PLO from 2007 through 2017 were reviewed. Among 43 women with annual follow-up dual-energy X-ray absorptiometry data for 3 years, 33 were treated with TPTD (median 12 months) with (TPTD-ART, n = 13; median, 18 months) or without (TPTD-no ART, n = 20) sequential ART. The two groups showed no differences in the mean age (31 vs. 31 years), body mass index (BMI, 20.5 vs. 21.0 kg/m2), and baseline lumbar spine (LS) BMD (0.666 vs. 0.707 g/cm2; p > 0.05 for all). LSBMD increased at 1, 2, and 3 years from baseline in both the TPTD-ART (14.1%, 21.8%, and 24.0%, respectively) and TPTD-no ART (17.3%, 24.1%, and 23.4%, respectively) groups, without significant between-group differences. Similar results were observed for the total hip BMD. LSBMD gain at 3 years did not differ by ART use (adjusted ß, 0.40; p = 0.874) in univariable and multivariable models adjusted for age, BMI, and baseline LSBMD. In summary, BMD gain by TPTD administration in premenopausal women with PLO can be well maintained without sequential ART treatment.

C-Arm Computed Tomography-Assisted Adrenal Venous Sampling Improved Right Adrenal Vein Cannulation and Sampling Quality in Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling (AVS) is a gold standard for subtype classification of primary aldosteronism (PA). However, this procedure has a high failure rate because of the anatomical difficulties in accessing the right adrenal vein. We investigated whether C-arm computed tomography-assisted AVS (C-AVS) could improve the success rate of adrenal sampling. METHODS: A total of 156 patients, diagnosed with PA who underwent AVS from May 2004 through April 2017, were included. Based on the medical records, we retrospectively compared the overall, left, and right catheterization success rates of adrenal veins during the periods without C-AVS (2004 to 2010, n=32) and with C-AVS (2011 to 2016, n=124). The primary outcome was adequate bilateral sampling defined as a selectivity index (SI) >5. RESULTS: With C-AVS, the rates of adequate bilateral AVS increased from 40.6% to 88.7% (P<0.001), with substantial decreases in failure rates (43.7% to 0.8%, P<0.001). There were significant increases in adequate sampling rates from right (43.7% to 91.9%, P<0.001) and left adrenal veins (53.1% to 95.9%, P<0.001) as well as decreases in catheterization failure from right adrenal vein (9.3% to 0.0%, P<0.001). Net improvement of SI on right side remained significant after adjustment for left side (adjusted SI, 1.1 to 9.0; P=0.038). C-AVS was an independent predictor of adequate bilateral sampling in the multivariate model (odds ratio, 9.01; P<0.001). CONCLUSION: C-AVS improved the overall success rate of AVS, possibly as a result of better catheterization of right adrenal vein.

Real-time monitoring and visualization of the multi-dimensional motion of an anisotropic nanoparticle.

As interest in anisotropic particles has increased in various research fields, methods of tracking such particles have become increasingly desirable. Here, we present a new and intuitive method to monitor the Brownian motion of a nanowire, which can construct and visualize multi-dimensional motion of a nanowire confined in an optical trap, using a dual particle tracking system. We measured the isolated angular fluctuations and translational motion of the nanowire in the optical trap, and determined its physical properties, such as stiffness and torque constants, depending on laser power and polarization direction. This has wide implications in nanoscience and nanotechnology with levitated anisotropic nanoparticles.

Constitutively active FOXO1 diminishes activin induction of Fshb transcription in immortalized gonadotropes.

In the present study, we investigate whether the FOXO1 transcription factor modulates activin signaling in pituitary gonadotropes. Our studies show that overexpression of constitutively active FOXO1 decreases activin induction of murine Fshb gene expression in immortalized LßT2 cells. We demonstrate that FOXO1 suppression of activin induction maps to the -304/-95 region of the Fshb promoter containing multiple activin response elements and that the suppression requires the FOXO1 DNA-binding domain (DBD). FOXO1 binds weakly to the -125/-91 region of the Fshb promoter in a gel-shift assay. Since this region of the promoter contains a composite SMAD/FOXL2 binding element necessary for activin induction of Fshb transcription, it is possible that FOXO1 DNA binding interferes with SMAD and/or FOXL2 function. In addition, our studies demonstrate that FOXO1 directly interacts with SMAD3/4 but not SMAD2 in a FOXO1 DBD-dependent manner. Moreover, we show that SMAD3/4 induction of Fshb-luc and activin induction of a multimerized SMAD-binding element-luc are suppressed by FOXO1 in a DBD-dependent manner. These results suggest that FOXO1 binding to the proximal Fshb promoter as well as FOXO1 interaction with SMAD3/4 proteins may result in decreased activin induction of Fshb in gonadotropes.

Serine 9 and tyrosine 216 phosphorylation of GSK-3ß differentially regulates autophagy in acquired cadmium resistance.

Glycogen synthase kinase-3ß (GSK-3ß) plays an important role in the regulation of apoptosis. To investigate its involvement in acquired cadmium (Cd) resistance, Cd-resistant cells (RH460) were established from H460 lung carcinoma cells. Cd resistance led to interruption of apoptosis and autophagy, as determined by an apoptotic sub-G1 population, procaspase-3 clevage, and LC3-II induction. Cd-induced autophagy preceded apoptosis as determined by 3-methyladenine or zVAD and time-course experiments after Cd treatment. Despite ß-catenin accumulation, phospho(p)-Ser/Tyr GSK-3α/ß increased in the nucleus until 12h after treatment and then p-Ser partly translocated to the cytoplasm. The GSK-3 inhibitor lithium augmented Cd-induced p-Ser GSK-3α/ß, which accumulated in the nucleus and cytoplasm, and increased autophagy. SB216763 inhibited p-Ser/p-Tyr GSK-3α/ß and subsequent autophagy. GSK-3ß knockdown decreased Cd-induced autophagy. Cd exposure to RH460 cells overexpressed with pcDNA-GSK-3ß-HA strongly phosphorylated Ser(9)/Tyr(216) residues and decreased LC3-II. Constitutively active pcDNA-GSK-3ß(S9A)-HA overexpression phosphorylated Tyr(216) and decreased LC3-II, suggesting that p-Tyr inhibits autophagy. PI3K inhibitors decreased Cd-induced p-Ser GSK-3αß and LC3-II, whereas a Ser/Thr phosphatase inhibitor, okadaic acid, hyperphosphorylated Ser residues, which accumulated in the nucleus and cytosol, and enhanced LC3-II. The general tyrosine kinase inhibitor genistein suppressed Cd-induced p-Tyr/p-Ser GSK-3α/ß and LC3-II. Mouse lung tissues respond to long-term Cd exposure increased p-Tyr, downregulated LC3-II, and accumulated full-length Bax and procaspase-3. Taken together, this study shows that acquired Cd resistance is regulated by GSK-3ß phosphorylation state, but not activation state, and intracellular localization of p-Ser GSK-3 regulates Cd-induced autophagy and apoptosis.

Using the developmental gene bicoid to identify species of forensically important blowflies (Diptera: calliphoridae).

Identifying species of insects used to estimate postmortem interval (PMI) is a major subject in forensic entomology. Because forensic insect specimens are morphologically uniform and are obtained at various developmental stages, DNA markers are greatly needed. To develop new autosomal DNA markers to identify species, partial genomic sequences of the bicoid (bcd) genes, containing the homeobox and its flanking sequences, from 12 blowfly species (Aldrichina grahami, Calliphora vicina, Calliphora lata, Triceratopyga calliphoroides, Chrysomya megacephala, Chrysomya pinguis, Phormia regina, Lucilia ampullacea, Lucilia caesar, Lucilia illustris, Hemipyrellia ligurriens and Lucilia sericata; Calliphoridae: Diptera) were determined and analyzed. This study first sequenced the ten blowfly species other than C. vicina and L. sericata. Based on the bcd sequences of these 12 blowfly species, a phylogenetic tree was constructed that discriminates the subfamilies of Calliphoridae (Luciliinae, Chrysomyinae, and Calliphorinae) and most blowfly species. Even partial genomic sequences of about 500 bp can distinguish most blowfly species. The short intron 2 and coding sequences downstream of the bcd homeobox in exon 3 could be utilized to develop DNA markers for forensic applications. These gene sequences are important in the evolution of insect developmental biology and are potentially useful for identifying insect species in forensic science.

Meralgia paresthetica affecting parturient women who underwent cesarean section -A case report-.

Meralgia paresthetica is commonly caused by a focal entrapment of lateral femoral cuteneous nerve while it passes the inguinal ligament. Common symptoms are paresthesias and numbness of the upper lateral thigh area. Pregnancy, tight cloths, obesity, position of surgery and the tumor in the retroperitoneal space could be causes of meralgia paresthetica. A 29-year-old female patient underwent an emergency cesarean section under spinal anesthesia without any problems. But two days after surgery, the patient complained numbness and paresthesia in anterolateral thigh area. Various neurological examinations and L-spine MRI images were all normal, but the symptoms persisted for a few days. Then, electromyogram and nerve conduction velocity test of the trunk and both legs were performed. Test results showed left lateral cutaneous nerve injury and meralgia paresthetica was diagnosed. Conservative treatment was implemented and the patient was free of symptoms after 1 month follow-up.

Anesthetic management for emergent craniotomy in a patient with Eisenmenger's syndrome: A case report.

Eisenmenger's syndrome describes the elevation of pulmonary arterial (PA) pressure to the systemic level caused by an increased pulmonary vascular resistance with reversed or bi-directional shunt through an intracardiac or aortopulmonary communication. We report a case of an emergent craniotomy for cerebellar abscess in a 21-year-old male patient with Eisenmenger syndrome secondary to Large VSD. A PA catheter was inserted via right femoral vein, but could not be advanced pass the pulmonic valve. After futile attempts to place the catheter tip in the right ventricle. Anesthesia was induced with etomidate, rocuronium, midazolam and fentanyl and maintained with only high dose fentanyl. Milinone and norepinephrine were infused continuously to decrease right to left shunt. He was transferred to the intensive care unit under intubated state and treated with antibiotics for a few days due to intermittent high fever. The operation ended without major complications and the patient was discharged 42 days later.