Genomic, transcriptomic, and metabolomic analysis of Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites.

Plants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles, and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound.

[Comparison of four-coagulation-tests values in normal pregnant women during early and late pregnancy and the influence of age].

Objective: To explore and compare the reference ranges of four coagulation tests in normal pregnant women during early and late pregnancy and the influence of age. Methods: Values of four coagulation tests from 4 974 pregnant women, who gave single birth at Peking University First Hospital, Obstetrics and Gynecology Hospital of Fudan University, West China Second University Hospital, Peking University Third Hospital and Shengjing Hospital of China Medical University from February 2017 to July 2020, were measured and analyzed in this study, including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and thrombin time (TT). The four normal reference ranges of coagulation during early and late pregnancy phases were expressed as P2.5-P97.5. The difference of two pregnancy phases was compared by non-parametric test of two related samples. And the difference between pregnant women of advanced and non-advanced age in the same pregnancy phase was compared by independent sample non-parametric test. Chi-square test was used to compare the incidence of pregnancy complications in different coagulation reference ranges. Results: The reference ranges of PT of normal pregnant women's early and late pregnancy were 10.0-13.9 s and 9.6-12.3 s, the reference ranges of APTT were 22.6-35.3 s and 22.4-30.9 s, the reference ranges of Fib were 2.4-5.0 g/L and 3.0-5.7 g/L, the reference ranges of TT were 12.0-19.0 s and 11.5-18.4 s. Compared with early pregnancy, PT, APTT and TT shortened significantly, while the Fib significantly increased in late pregnancy (all P<0.001). PT, APTT and TT of advanced and non-advanced age pregnant women were significantly different (all P<0.01). Compared with the ranges of non-pregnant population, more pregnant women were included in the normal pregnant reference ranges of PT in early pregnancy and APTT in the early and late pregnancy, while the incidence of pregnancy complications had no significant differences (all P>0.05). The incidence of fetal distress was higher and the incidence of preterm birth was lower in the reference range of PT in late pregnancy. The incidence of gestational diabetes mellitus was higher in the early and late gestational Fib reference ranges, and the incidence of hypertensive disorders in pregnancy was higher in the late gestational Fib reference range (all P<0.05). Conclusions: The coagulation function of pregnant women increases significantly with the growth of pregnancy, and there is a significant difference between advanced significantly and non-advanced age pregnant women. The recommended ranges of normal pregnant women's early and late pregnancy PT are 10.0-13.9 s and 9.6-12.3 s, the recommended ranges of APTT are 22.6-35.3 s and 22.4-30.9 s, the recommended ranges of TT are 12.0-19.0 s and 11.5-18.4 s. The appropriate ranges of normal pregnant women's early and late pregnancy Fib still need further exploration.

Comparison of oncological outcomes after open and laparoscopic re-resection of incidental gallbladder cancer.

BACKGROUND: The safety and oncological efficacy of laparoscopic re-resection of incidental gallbladder cancer have not been studied. This study aimed to compare laparoscopic with open re-resection of incidentally discovered gallbladder cancer while minimizing selection bias. METHODS: This was a multicentre retrospective observational cohort study of patients with incidental gallbladder cancer who underwent re-resection with curative intent at four centres between 2000 and 2017. Overall survival (OS) and recurrence-free survival (RFS) were analysed by intention to treat. Inverse probability of surgery treatment weighting using propensity scoring was undertaken. RESULTS: A total of 255 patients underwent re-resection (190 open, 65 laparoscopic). Nineteen laparoscopic procedures were converted to open operation. Surgery before 2011 was the only factor associated with conversion. Duration of hospital stay was shorter after laparoscopic re-resection (median 4 versus 6 days; P < 0·001). Three-year OS rates for laparoscopic and open re-resection were 87 and 62 per cent respectively (P = 0·502). Independent predictors of worse OS were residual cancer found at re-resection (hazard ratio (HR) 1·91, 95 per cent c.i. 1·17 to 3·11), blood loss of at least 500 ml (HR 1·83, 1·23 to 2·74) and at least four positive nodes (HR 3·11, 1·46 to 6·65). In competing-risks analysis, the RFS incidence was higher for laparoscopic re-resection (P = 0·038), but OS did not differ between groups. Independent predictors of worse RFS were one to three positive nodes (HR 2·16, 1·29 to 3·60), at least four positive nodes (HR 4·39, 1·96 to 9·82) and residual cancer (HR 2·42, 1·46 to 4·00). CONCLUSION: Laparoscopic re-resection for selected patients with incidental gallbladder cancer is oncologically non-inferior to an open approach. Dissemination of advanced laparoscopic skills and timely referral of patients with incidental gallbladder cancer to specialized centres may allow more patients to benefit from this operation.

ANTECEDENTES: No se conoce la seguridad y la eficacia oncológica de la re-resección laparoscópica del cáncer incidental de vesícula biliar. Este estudio tiene como objetivo comparar las re-resecciones del cáncer incidental de vesícula biliar por vía laparoscópica y vía abierta, minimizando el sesgo de selección. MÉTODOS: Estudio de cohortes observacional, retrospectivo y multicéntrico de pacientes con cáncer incidental de vesícula biliar que se sometieron a una re-resección con intención curativa en 4 centros entre 2000 y 2017. Se analizó la supervivencia global (overall survival, OS) y la supervivencia libre de recidiva (recurrence free survival, RFS) según intención de tratamiento. Se calculó la probabilidad inversa de la ponderación del tratamiento quirúrgico utilizando puntuación de propensión. RESULTADOS: Se incluyeron 255 pacientes con re-resección (190 por vía abierta y 65 por vía laparoscópica). Se convirtieron 19 pacientes del grupo laparoscópico. El único factor relacionado con la conversión fue la realización de la cirugía antes de año 2011. La mediana de la estancia hospitalaria fue más corta tras la re-resección laparoscópica (4 versus 6 días; P < 0,001). La OS a tres años fue del 87% y del 62% (P = 0,502) para las re-resecciones laparoscópicas y abiertas, respectivamente). Los factores predictivos independientes relacionados con una peor OS fueron el hallazgo de cáncer residual en el momento de la re-resección (cociente de riesgos instantáneos, hazard ratio, HR 1,91; i.c. del 95% 1,17-3,11), una pérdida hemática > 500 ml (HR 1,83; i.c. del 95% 1,23-2,74) y la presencia de ≥ 4 ganglios positivos (HR 3,11; i.c. del 95% 1,46-6,65). En el análisis de riesgo competitivo, la RFS fue mayor para la resección laparoscópica (P = 0,038), pero no hubo diferencias en la OS entre ambos grupos. Los factores predictivos independientes de peor RFS fueron la detección de 1-3 ganglios positivos (HR 2,16; i.c. del 95% 1,29-3,60), ≥ 4 ganglio positivos (HR 4,39; i.c. del 95% 1,96-9,82) y el cáncer residual (HR 2,42; i.c. de 95% 1,46-4,0). CONCLUSIÓN: En pacientes seleccionados, los resultados oncológicos de la re-resección laparoscópica de un cáncer incidental de vesícula biliar no son inferiores a los que se obtienen por vía abierta. Una mayor difusión de las técnicas laparoscópicas avanzadas y una oportuna derivación de los pacientes con cáncer de vesícula biliar incidental a centros especializados podrían permitir que un mayor número de pacientes se beneficiaran de este abordaje.

Randomized clinical trial of accelerated enhanced recovery after minimally invasive colorectal cancer surgery (RecoverMI trial).

BACKGROUND: Minimally invasive surgery (MIS) and enhanced recovery protocols (ERPs) have improved postoperative recovery and shortened length of hospital stay (LOS). Telemedicine technology has potential to improve outcomes and patient experience further. This study was designed to determine whether the combination of MIS, ERP and a structured telemedicine programme (TeleRecovery) could shorten total 30-day LOS by 50 per cent. METHODS: This was a phase II prospective RCT at a large academic medical centre. Eligible patients aged 18-80 years undergoing minimally invasive colorectal resection using an ERP were randomized after surgery. The experimental arm (RecoverMI) included accelerated discharge on postoperative day (POD) 1 with or without evidence of bowel function and a televideoconference on POD 2. The control arm was standard postoperative care. The primary endpoint was total 30-day LOS (postoperative stay plus readmission/emergency department/observation days). Secondary endpoints included patient-reported outcomes measured by EQ-5D-5L™, Brief Pain Inventory (BPI) and a satisfaction questionnaire. RESULTS: Thirty patients were randomized after robotic (21 patients) or laparoscopic (9) colectomy, including 14 patients in the RecoverMI arm. Median 30-day total LOS was 28·3 (i.q.r. 23·7-43·6) h in the RecoverMI arm and 51·5 (43·8-67·0) h in the control arm (P = 0·041). There were no differences in severe adverse events or EQ-5D-5L™ score between the study arms. The BPI revealed low pain scores regardless of treatment arm. Satisfaction was high in both arms. CONCLUSION: In patients having surgery for colorectal neoplasms, the trimodal combination of MIS, ERP and TeleRecovery can reduce 30-day LOS while preserving patients' quality of life and satisfaction. Registration number: NCT02613728 ( https://clinicaltrials.gov).

ANTECEDENTES: La cirugía mínimamente invasiva (minimally invasive surgery, MIS) y los protocolos de recuperación intensificada (enhanced recovery protocols, ERP) han mejorado la recuperación postoperatoria y acortan la duración de la estancia (length of stay, LOS). La tecnología de la telemedicina tiene potencial para mejorar aún más los resultados y la experiencia del paciente. Este estudio se diseñó para determinar si la combinación de MIS, ERP y un programa estructurado de telemedicina (TeleRecovery) podría acortar la LOS total a los 30 días en un 50%. MÉTODOS: Se efectuó un ensayo controlado aleatorizado, prospectivo, de fase II en un gran centro médico académico. Los pacientes elegibles de 18-80 años de edad que se sometieron a resección colorrectal MIS mediante ERP se asignaron al azar después de la resección quirúrgica. El brazo experimental (RecoverMI) incluyó el alta acelerada en el día 1 del postoperatorio (postoperative day, POD) con o sin evidencia de recuperación del tránsito intestinal y una televideoconferencia en el día 2 POD. Los pacientes en el grupo control recibieron los cuidados postoperatorios habituales. El criterio de valoración principal fue la LOS total (estancia postoperatoria más reingreso/estancia en urgencias/días de observación) a los 30 días. Los criterios de valoración secundarios incluyeron los resultados referidos por los pacientes medidos por los cuestionarios EQ-5D-5L, el Cuestionario Breve del Dolor (Brief Pain Inventory, BPI) y un cuestionario de satisfacción. RESULTADOS: Treinta pacientes fueron aleatorizados después de una colectomía robótica (21) o laparoscópica (9), incluidos 14 pacientes en el grupo de RecoverMI. La mediana de la LOS total a los 30 días fue de 28,3 horas (rango intercuartílico, RIQ 23,7-43,6) en el grupo de RecoverMI y de 51,5 horas (RIQ 43,8-67,0) en el grupo control (P = 0,04). No hubo diferencias entre los grupos de estudio en los eventos adversos graves o en las puntuaciones del EQ-5D-5L. El BPI mostró puntuaciones bajas de dolor independientemente del grupo de tratamiento. La satisfacción fue alta en ambos grupos. CONCLUSIÓN: Entre los pacientes que se someten a cirugía por cáncer colorrectal, la combinación trimodal de MIS, ERP y TeleRecovery puede reducir la LOS a los 30 días, preservando la calidad de vida y la satisfacción del paciente.

Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways.

AIM: To investigate the effects of vascular endothelial growth factor A (VEGFA) and the underlying molecular mechanisms on the migration of human dental pulp stem cells (hDPSCs). METHODOLOGY: The expression of VEGFA in inflammatory pulp tissue and lipopolysaccharide (LPS)-stimulated dental pulp cells was examined by immunofluorescence staining and qRT-PCR. The migration of hDPSCs was detected using transwell migration and wound healing assays. The activation of FAK, PI3K, Akt and p38 signalling was evaluated by Western blot analysis. Silence RNA (siRNA) technology was utilized to knockdown the expression of VEGFR1 (Flt-1) and VEGFR2 (Flk-1/KDR). PF573228 (inhibitor of FAK), LY294002 (inhibitor of PI3K), SB203580 (inhibitor of p38) and SU5416 (inhibitor of VEGFR2) were employed to investigate the effect of VEGFA on the migratory mechanism of hDPSCs. Data were analysed statistically using the Student's t-test or one-way ANOVA. RESULTS: The expression levels of VEGFA in inflammatory pulp tissue in vivo and LPS-stimulated dental pulp cells in vitro were significantly greater than those in the control groups (P < 0.05). Vascular endothelial growth factor A promoted the migration of hDPSCs in a concentration-dependent manner. Several signalling pathways, including FAK, PI3K, Akt and p38, were activated by VEGFA in a dose- and time-dependent manner in hDPSCs. The VEGFA-induced migration of hDPSCs was significantly inhibited with drug inhibitors such as PF573228, LY294002, SB203580 or SU5416 (P < 0.05). These signalling pathways activated by VEGFA stimulation were significantly suppressed by pre-treatment with inhibitor of VEGFR2 (SU5416) or transfection with siRNA of VRGFR2 (P < 0.05) but not VEGFR1 siRNA. CONCLUSIONS: Vascular endothelial growth factor A/VEGFR2 axis promoted the migration of hDPSCs via the FAK/PI3K/Akt and p38 MAPK signalling pathways. These findings reveal a novel molecular mechanism for cell migration of hDPSCs, which may contribute to the remodelling of pulp tissue and dentine.

Lipopolysaccharide-induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells.

AIM: To investigate the role of GATA-binding protein 4 (GATA4) in the inflammatory response induced by DNA double-strand breaks (DSBs) in human dental pulp cells (hDPCs). METHODOLOGY: Lipopolysaccharide (LPS) was used for stimulating inflammation in dental pulp tissue in vivo and hDPCs in vitro. Expression levels of GATA4 and γ-H2A.X (a marker for DSBs) were detected at different stages of pulpitis in a rat model and human pulp tissues by immunohistochemistry. Real-time quantitative polymerase chain reaction and Western blot were performed to assess expression of GATA4 and γ-H2A.X and the activation of nuclear factor κB (NF-κB) in hDPCs stimulated by LPS. The comet assay was used for detecting the extent of DSBs in hDPCs. Immunocytochemistry and Western blot were utilized to evaluate expression of γ-H2A.X and GATA4 and activation of NF-κB in hDPCs pre-treated with inhibitors of DNA damage response or transfected with GATA4 small interfering RNA before the treatment of LPS. Data were analysed statistically using one-way anova or Kruskal-Wallis tests. RESULTS: The expression of GATA4 and activation of DNA damage response and NF-κB in inflamed pulp tissue and LPS-treated hDPCs were identified. Significantly decreased expression of GATA4 and significantly decreased inflammatory processes in hDPCs were demonstrated via suppression of DNA damage response (P < 0.05). In GATA4-knockdown cells, the expression of γ-H2A.X did not change, but nuclear translocation of p65 was significantly suppressed (P < 0.05) upon induction by LPS. CONCLUSIONS: Lipopolysaccharide-induced DSBs activated the NF-κB signalling pathway in hDPCs, and GATA4 acts as a positive moderator of the progress. The involvement of GATA4 in this pathology may serve as a therapeutic target in pulpitis.

Diode-wing-pumped electro-optically Q-switched 2 µm laser with pulse energy scaling over ten millijoules.

Characteristics of diode-wing-pumped highly efficient Tm:LuAG lasers running both in continuous wave (CW) and electro-optical Q-switching regimes have been investigated. Using a simple plane-plane cavity, a maximum CW output power of 8.5 W has been achieved with a corresponding slope efficiency of 44.5% by "wing pumping" at 790 nm. With a V-shaped cavity, a diode-wing-pumped MgO:LiNbO3 crystal based electro-optically Q-switched Tm:LuAG laser at 2022.9 nm delivered a maximum pulse energy of 10.8 mJ and a minimum pulse width of 52 ns at a corresponding repetition rate of 100 Hz. To the best of our knowledge, the achieved CW output power and Q-switched pulse energy have both set records for all-solid-state Tm:LuAG lasers, which well reveals an efficient way to generate high-power and high-energy lasers at 2 µm wavelength.

[Effects of menopausal factor on fine anatomy of bladder urethra and vagina in women undergoing vaginal delivery].

Objective: To explore the effects of menopausal factor on fine anatomy of bladder, urethra and vagina in women undergoing vaginal delivery. Methods: Gynecological patients in Nanfang hospital from January 2013 to October 2016 were collected, and then the patients whose MRI images quality meet the require of reconstruction, with the history of vaginal delivery experience, without any cesarean section experience, and the first labor time was ≤30 years old were enrolled. The patients who had pelvic floor dysfunction when done MRI examinations were excluded. Finally, 238 cases were randomly selected out, and 238 models of data were reconstructed and measured by Mimics and UG software. The independent t test was used to do the comparison between menopausal group and those not yet menopause. Results: First, we built 238 3D models totally. Second, the parameters related with bladder and urethra: the angle of bladder and urethra, ß angle, urethra pubic angle, α angle, retropubic space, the length between bladder neck and edge of pubic midpoint, and urethral striated muscle thickness of menopausal group were bigger than those of pre-menopausal group. While for the urethra tilt angle, the former group was smaller than that of the latter group. But there was no significant statistical differences between two groups. Third, the parameters related with vagina: the proximal urethral vaginal gap of the post-menopause group was smaller than that of pre-menopausal group, while for the middle and distal urethral vaginal gap, the former group was bigger than that of the latter group. The length and width of vaginal anterior wall of the post-menopausal group were smaller than those of pre-menopausal group. Beside the middle urethral vaginal gap, all the difference between two groups had no statistical meaning. The 2D shape of axial vaginal, H type occupation of the former group was obviously lower than that of the latter group. Conclusions: Menopause has an effect on fine anatomy of pelvic organ. Especially on the shape of vagina, the middle urethral vaginal gap become much wider after menopause, the occupation of shallow concave type become much higher post-menopausal. It means the lateral and backward support function of the urethra and vagina is relatively weakened after menopausal, and the shape of vagina become smaller.

Identification and characterization a novel HLA-A allele, A*02:355, by sequence-based typing in a Chinese potential donor.

The new allele A*02:355 differs from A* 02:03:01 at positions 98 (T→A) and 102(A→C) resulting in an amino acid exchange F9→T. Interallelic sequence exchange is more likely the mechanism of its origination. The amino acid replacement influences the HLA peptide binding cleft and might have significant functional effects.

Long-term blood glucose monitoring with implanted telemetry device in conscious and stress-free cynomolgus monkeys.

AIMS: Continuous blood glucose monitoring, especially long-term and remote, in diabetic patients or research is very challenging. Nonhuman primate (NHP) is an excellent model for metabolic research, because NHPs can naturally develop Type 2 diabetes mellitus (T2DM) similarly to humans. This study was to investigate blood glucose changes in conscious, moving-free cynomolgus monkeys (Macaca fascicularis) during circadian, meal, stress and drug exposure. MATERIALS AND METHODS: Blood glucose, body temperature and physical activities were continuously and simultaneously recorded by implanted HD-XG telemetry device for up to 10 weeks. RESULTS AND DISCUSSION: Blood glucose circadian changes in normoglycemic monkeys significantly differed from that in diabetic animals. Postprandial glucose increase was more obvious after afternoon feeding. Moving a monkey from its housing cage to monkey chair increased blood glucose by 30% in both normoglycemic and diabetic monkeys. Such increase in blood glucose declined to the pre-procedure level in 30 min in normoglycemic animals and >2 h in diabetic monkeys. Oral gavage procedure alone caused hyperglycemia in both normoglycemic and diabetic monkeys. Intravenous injection with the stress hormones, angiotensin II (2 µg/kg) or norepinephrine (0.4 µg/kg), also increased blood glucose level by 30%. The glucose levels measured by the telemetry system correlated significantly well with glucometer readings during glucose tolerance tests (ivGTT or oGTT), insulin tolerance test (ITT), graded glucose infusion (GGI) and clamp. CONCLUSION: Our data demonstrate that the real-time telemetry method is reliable for monitoring blood glucose remotely and continuously in conscious, stress-free, and moving-free NHPs with the advantages highly valuable to diabetes research and drug discovery.

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer.

BACKGROUND: High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations. METHODS: We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used. RESULTS: High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR. CONCLUSIONS: High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.

1.21 W passively mode-locked Tm:LuAG laser.

A watt-level output passively mode-locked Tm:LuAG bulk laser with an InGaAs semiconductor saturable absorber mirror (SESAM) is demonstrated for the first time. A maximum average output power of 1.21 W at 2022.9 nm has been achieved with a pulse duration of 38 ps and a repetition rate of 129.2 MHz. The results indicate the potential of Tm:LuAG crystals as candidate for realizing high power ultrafast lasers at 2 µm.

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer.

BACKGROUND: Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor. METHODS: Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients. RESULTS: A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5). CONCLUSION: Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

Diode-pumped continuous wave and passively Q-switched Tm, Mg: LiTaO3 lasers.

We have demonstrated the continuous wave and passively Q-switched Tm, Mg: LiTaO3 lasers for the first time. In continuous wave (CW) regime, a maximum CW output power of 1.03 W at 1952 nm was obtained, giving a slope efficiency of 9.5% and a beam quality M2 = 2.2. In passive Q-switching regime, a single walled carbon nanotube (SWCNT) was employed as saturable absorber (SA). The Tm,Mg:LiTaO3 laser has yielded a pulse of 560 ns under repetition rate of 34.2 kHz at 1926 nm, corresponding to a single pulse energy of 10.1 µJ. The results indicate a promising potential of nonlinear crystals in the applications for laser host materials.

Establish and verify TSH reference intervals using optimized statistical method by analyzing laboratory-stored data.

OBJECTIVE: To establish reference intervals using an optimized statistical method by collecting available laboratory data of thyroid stimulating hormone (TSH), and then to verify with the laboratory-present reference intervals. METHODS: TSH RIs of the total population and different races, genders, age, source of sample are established through improved Hoffmann and Katayev's method with TSH test results data from Jan 2010 to April 2012 were collected, and finally conduct comparative verification with the laboratory present RIs. RESULTS: According to the improved method, we get various RIs of different sample populations. On comparing with the laboratory current RI (0.270-4.200 mIU/L) most reference change values (RCV) were within acceptable limits. Only lower limit of Han male, Uygur male and out-patient male populations outwith acceptable limits. On excluding the different values, finally, the new RI by the optimized statistical method is 0.233-4.979 mIU/L. Because the new RI expanded the current RI and was not different from the current RI, it was indicated that new RI could be used to verify the laboratory current RIs and seen as the current RI's confidence interval (CI). INFERENCE: TSH RIs established by optimized Hoffmann's and Katayev's methods is viable and can be used to verify RIs provided by manufacturers or other laboratories.

Broadly wavelength tunable acousto-optically Q-switched Tm:Lu2SiO5 laser.

A broadly wavelength tunable acousto-optically Q-switched Tm:Lu2SiO5 (Tm:LSO) laser is presented for the first time, to our best knowledge. The emission wavelength was tuned in a broad spectral region over 111 nm ranging from 1959 to 2070 nm. A shortest pulse duration of 345 ns with beam quality of M(2)≤1.65 was obtained at pulse repetition frequency (PRF) of 1 kHz, corresponding to a maximum single pulse energy of 0.26 mJ and peak power of 0.75 kW. The experimental results indicated that Tm:LSO crystal has outstanding potential for obtaining broadly wavelength tunable and low-PRF laser pulses at 2 µm.

Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset.

BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.

PIEZO1 Promotes Odontoblast-Mediated Reactionary Dentinogenesis via SEMA3A.

Located at the interface of the dentin-pulp complex, the odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis and the underlying mechanisms remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in healthy human third molars, mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. In addition, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in odontoblast-mediated reactionary dentinogenesis, mice with a conditional knockout of Piezo1 in odontoblasts were generated, and no significant differences in teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair by odontoblasts. In summary, these findings suggest that PIEZO1 enhances the mineralization capacity of hOBLCs in vitro via the Ca2+/PI3K-Akt/SEMA3A signaling pathway and contributes to reactionary dentinogenesis in vivo.

Diode-pumped continuous wave tunable and graphene Q-switched Tm:LSO lasers.

We have investigated the lasing characteristics of Tm:LSO crystal in three operation regimes: continuous wave (CW), wavelength tunable and passive Q-switching based on graphene. In CW regime, a maximum output power of 0.65 W at 2054.9 nm with a slope efficiency of 21% was achieved. With a quartz plate, a broad wavelength tunable range of 145 nm was obtained, corresponding to a FWHM of 100 nm. By using a graphene saturable absorber mirror, the passively Q-switched Tm:LSO laser produced pulses with duration of 7.8 µs at 2030.8 nm under a repetition rate of 7.6 kHz, corresponding to pulse energy of 14.0 µJ.