Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.

Early committed polarization of intracellular tension in response to cell shape determines the osteogenic differentiation of mesenchymal stromal cells.

Within the heterogeneous tissue architecture, a comprehensive understanding of how cell shapes regulate cytoskeletal mechanics by adjusting focal adhesions (FAs) signals to correlate with the lineage commitment of mesenchymal stromal cells (MSCs) remains obscure. Here, via engineered extracellular matrices, we observed that the development of mature FAs, coupled with a symmetrical pattern of radial fiber bundles, appeared at the right-angle vertices in cells with square shape. While circular cells aligned the transverse fibers parallel to the cell edge, and moved them centripetally in a counter-clockwise direction, symmetrical bundles of radial fibers at the vertices of square cells disrupted the counter-clockwise swirling and bridged the transverse fibers to move centripetally. In square cells, the contractile force, generated by the myosin IIA-enriched transverse fibers, were concentrated and transmitted outwards along the symmetrical bundles of radial fibers, to the extracellular matrix through FAs, and thereby driving FA organization and maturation. The symmetrical radial fiber bundles concentrated the transverse fibers contractility inward to the linkage between the actin cytoskeleton and the nuclear envelope. The tauter cytoskeletal network adjusted the nuclear-actomyosin force balance to cause nuclear deformability and to increase nuclear translocation of the transcription co-activator YAP, which in turn modulated the switch in MSC commitment. Thus, FAs dynamically respond to geometric cues and remodel actin cytoskeletal network to re-distribute intracelluar tension towards the cell nucleus, and thereby controlling YAP mechanotransduction signaling in regulating MSC fate decision. STATEMENT OF SIGNIFICANCE: We decipher how cellular mechanics is self-organized depending on extracellular geometric features to correlate with mesenchymal stromal cell lineage commitment. In response to geometry constrains on cell morphology, symmetrical radial fiber bundles are assembled and clustered depending on the maturation state of focal adhesions and bridge with the transverse fibers, and thereby establishing the dynamic cytoskeletal network. Contractile force, generated by the myosin-IIA-enriched transverse fibers, is transmitted and dynamically drives the retrograde movement of the actin cytoskeletal network, which appropriately adjusts the nuclear-actomyosin force balance and deforms the cell nucleus for YAP mechano-transduction signaling in regulating mesenchymal stromal cell fate decision.

Effect of Body Mass Index in Coronary CT Angiography Performed on a 256-Slice Multi-Detector CT Scanner.

We aimed to investigate the effect of a patient's body mass index (BMI) on radiation dose and image quality in prospectively ECG-triggered coronary CT angiography (CCTA) performed on a 256-slice multi-detector CT scanner. In total, 87 consecutive patients receiving CCTA examinations acquired with tube current modulation (TCM) and iterative reconstruction (IR) were enrolled in this study. The dose report recorded from the CT scanner console was used to derive the effective dose for patients. Subjective image quality scoring and objective noise measurements were conducted to quantify the impact of BMI on the image quality of CCTA. Because of the TCM technique, we expected tube current and radiation dose to increase as BMI increased. However, using TCM did not always guarantee sufficient radiation exposure to achieve consistent image quality for overweight or obese patients since the maximum X-ray tube output in milliamperes and kilovoltage peak was reached. The impact of photon starvation noise on image quality was not significant until BMI ≥ 27 kg/m2; this result could be due to IR's noise reduction capability. Our results also suggest that using TCM with a noise index of 25 HU can reduce radiation dose without compromising image quality compared to images obtained based on the manufacturer's default settings.

Comparisons of cancer detection rate and complications between transrectal and transperineal prostate biopsy approaches - a single center preliminary study.

BACKGROUND: Prostate biopsy remains the gold standard approach to verify prostate cancer diagnosis. Transrectal (TR) biopsy is a regular modality, while transperineal (TP) biopsy is an alternative for the patients who display persistently high levels of prostate-specific antigen (PSA) and thus have to undergo repeat biopsy. This study aimed to compare the cancer detection rates between TR and TP approaches and assess the post-bioptic complications of the two procedures. Besides, the feasibility of performing TP biopsies under local anesthesia was also evaluated. METHODS: A total of 238 outpatient visits meeting the criteria for prostate cancer biopsy were enrolled for this study. They were divided into two groups: the TP group (n = 130) consists of patients destined to undergo local anesthetic TP biopsy; and the TR group (n = 108) contained those who received TR biopsy as comparison. Age, PSA level, digital rectal exam (DRE) finding, prostate volume, and biopsy core number were used as the parameters of the multivariable analyses. The comparable items included cancer detection rate, complication rate, admission rate and visual analog scale (VAS) score. RESULTS: The cancer detection rates between TP and TR groups were quite comparable (45% v.s. 49%) (p = 0.492). However, the TP group, as compared to the TR group, had significantly lower incidence of infection-related complications (except epididymitis and prostatitis) that commonly occur after biopsies. None of the patients in the TP group were hospitalized due to the post-bioptic complications, whereas there was still a minor portion of those in the TR group (7.4%) requiring hospitalization after biopsy. Medians (25-75% quartiles) of visual analog scale (VAS) were 3 [3, 4] and 4 [3-5] respectively for the TP and TR procedures under local anesthesia, but no statistical significance existed between them (p = 0.085). CONCLUSIONS: Patients receiving TP biopsy are less likely to manifest infection-related complications. Therefore, TP biopsy is a more feasible local anesthetic approach for prostate cancer detection if there are concerns for infectious complications and/or the risk of general anesthesia.

Does preoperative percutaneous nephrostomy insertion worsen upper-tract urothelial cancer oncological outcome? A retrospective single center study.

BACKGROUND: Physicians doubt percutaneous nephrostomy (PCN) insertion on cancer related hydronephrosis patients causes tumor seeding and worse cancer control. In this article, we attempted to determine if preoperative PCN alters cancer control in upper tract urothelial cancer (UTUC) patients. METHODS: Retrospective analysis of UTUC patients in a single center from 2005 to 2015. Exclusion criteria included lymph node metastasis, and patients underwent perioperative adjuvant chemotherapy or radiotherapy. There were 664 patients in this analysis, with clinico-pathological data being collected retrospectively for Cox-regression statistical analysis. Outcomes were measured by local recurrence, distant metastasis and cancer-specific death with Kaplan-Meier curves. RESULTS: There were respectively 25 and 639 UTUC cancers in the preoperative PCN and non-PCN insertion groups with mean follow-up duration of 37.9 and 48.6 months, respectively. The preoperative PCN group consisted of 17 patients (68%) with tumor located in the ureter, while the PCN-negative group included 236 patients (36%) with tumor located in the ureter being statistically significant. These two groups were comparable in gender, age, follow-up duration, tumor stage, and pathological features of the UTUC. As for the cancer control in the PCN group, 4(16%), 1(4%) and 1(4%) had local recurrence, distant metastasis and cancer-specific death respectively; in the non-PCN group, 101(15.8%), 96(15%) and 72(11.2%) exhibited local recurrence, distant metastasis and cancer-specific death respectively. Statistical analysis showed no difference in oncologic outcomes between these two groups.(p = 0.804, 0.201 and 0.254). CONCLUSIONS: Preoperative percutaneous nephrostomy on upper-tract urothelial cancer poses little risk on tumor seeding and could be considered as part of treatment strategy if renal function preservation is needed.

A novel endoscopic classification for craniopharyngioma based on its origin.

Endoscopic endonasal approach for craniopharyngioma (CP) resection provides a wide view and direct observation of hypothalamus and origin of tumor. Under endoscopy, 92 CPs were classified into 2 types: Peripheral and Central, according to its relation to pituitary stalk. Peripheral type was further divided into 3 subtypes: Hypothalamic stalk, Suprasellar stalk and Intrasellar stalk CP, according to the different origin site along hypothalamus-pituitary axis. Peripheral type arisen from the stalk but expanded and grown laterally in an exophytic pattern, accounting for 71.7% of all CPs, preservation rate of stalk was higher (76.0%). Central type grew within and along pituitary stalk and located strictly in the midline. The pituitary stalk was hardly preserved (only15.4%). Hypothalamic stalk CPs (n = 36, 54.6%) developed from the junction of hypothalamus and stalk, hypothalamus damage was found in all of this subtype after surgery. Suprasellar stalk CPs (n = 14, 21.2%) originated from the lower portion of stalk and displaced hypothalamus upward rather than infiltrated it. Intrasellar stalk CPs (n = 16, 24.2%) arose from the subdiaphragma portion of the stalk, with less hypothalamus damage. Recoginzing the origin of CP is helpful to understand its growth pattern and relation to hypothalamus, which is critical in planning the most appropriate surgical approach and degree of excision.

Endoscopic Endonasal Clipping of Anterior Circulation Aneurysm: Surgical Techniques and Results.

BACKGROUND: Endoscopic endonasal clipping of intracranial aneurysms may use microsurgical techniques as an alternative to the transcranial approach. Here we report a series of patients who underwent microsurgical clipping of anterior circulation aneurysms via an endoscopic endonasal approach (EEA). METHODS: This retrospective chart review included all the patients who underwent standard binostril EEA for aneurysm clipping. Surgical outcomes and complications are noted. The rationality and limitations of this procedure are discussed. RESULTS: Seven patients with 12 aneurysms of the anterior circulation underwent EEA for clipping. These 12 aneurysms consisted of 5 anterior communicating artery (AComA) aneurysms, 4 paraclinoid aneurysms, 1 ophthalmic artery aneurysm, and 2 aneurysm located in the cavernous segment of internal carotid artery (ICA). Nine of the 12 aneurysms were successfully clipped. One giant paraclinoid aneurysm could not be clipped during operation and was coiled in second endovascular stage. The 2 aneurysms located in the cavernous segment of ICA were not clipped intentionally in a single-stage procedure, after weighing the surgical benefit against the difficulty of surgical exposure and feasibility. The proximal control of ICA was achieved in all cases. There was no death, no cerebrospinal fluid leak, or other complications. All patients recovered completely. CONCLUSIONS: EEA can provide direct access for microsurgical clipping of strictly selected anterior circulation aneurysms. All the principles of cerebrovascular surgery must be followed. These procedures require a long learning curve. Only teams with adequate experience in microvascular and endoscopic skull base surgeries should attempt this approach for treating aneurysms.

FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice.

Despite advances in antibiotic therapy and intensive care, the mortality caused by systemic inflammatory response syndrome and severe sepsis remains high. The use of anti-inflammatory agents to attenuate inflammatory response during acute systemic inflammatory reactions may improve survival rates. Here we show that a newly synthesized 2-pyridone compound (FJU-C4) can suppress the expression of late inflammatory mediators such as iNOS and COX-2 in murine macrophages. The pro-inflammatory cytokines, including TNFα, IL-1ß, and IL-6, were dose-dependently suppressed by FJU-C4 both in mRNA and protein levels. In addition, the expression of TNFα was inhibited from as early as 2 hours after exposure to LPS stimulation. The production of mature pro-inflammatory cytokines was also suppressed by pretreatment with FJU-C4 in either cell culture medium or mice serum when stimulated by LPS. FJU-C4 prolongs mouse survival and prevents mouse death from LPS-induced systemic inflammation when the dose of FJU-C4 is over 5 mg/kg. The activities of ERK, JNK, and p38MAPK were induced by LPS stimulation on murine macrophage cell line, but only p38MAPK signaling was dramatically suppressed by pretreatment with the FJU-C4 compound in a dose-dependent manner. NF-κB activation also was suppressed by FJU-C4 compound. These findings suggest that the FJU-C4 compound may act as a promising therapeutic agent against inflammatory diseases by inhibiting the p38MAPK and NF-κB signaling pathway.