Nonpalpable breast masses: One-year ultrasound follow-up and morbidity outcomes in Shanghai.

Women with nonpalpable breast masses are at a high risk of developing breast cancer (BC) due to misdiagnosis during the follow-up period.A total of 40,334 women were divided into palpable and nonpalpable breast mass groups. We assessed the risk factors for cancer development in patients with nonpalpable breast masses during a 1-year follow-up period.Of the 1335 patients in the nonpalpable breast mass group, we found 50 patients of BC, of which 35 patients accepted surgery and were confirmed with biopsy at the beginning of the study. The remaining 15 (1.1%) were diagnosed with BC during follow-up, and included 10 in situ and 5 invasive carcinomas. Four of the 10 patients in the in situ subgroup, and 2 out of the 5 in the invasive subgroup were overweight (Body mass index > 24 kg/m). Nine in situ BC patients had breast-conserving surgery, 1 had a mastectomy. No patient in the in situ group received chemotherapy or radiotherapy. All 5 patients with invasive disease received 6 cycles of chemotherapy. Only 3 (20%) of the 15 patients with BC had a positive family history. We found 131 BC cases, including BC detected during screening (81) and follow-up (50). The incidence of BC was 240.2 per 100,000 inhabitants.Patients with nonpalpable breast masses require regular follow-up as they have a high risk of cancer occurrence. Regular follow-up can lead to early diagnosis and effective treatment of these early-stage BC patients.

HMGB3 silence inhibits breast cancer cell proliferation and tumor growth by interacting with hypoxia-inducible factor 1α.

Background: Breast cancer is the most common malignant tumor that affects women with higher incidence. High-mobility group box 3 (HMGB3) plays critical functions in DNA repair, recombination, transcription and replication. This study aimed to investigate the effects of HMGB3 silence on mammosphere formation and tumor growth of breast cancer. Methods: LV5-HMGB3 and LV3-siHMGB3 vectors were transfected into MCF10A, MDA-MB-231, HCC1937, ZR-75-1 and MCF7 cells. Cell counting kit-8 (CCK-8) assay was used to evaluate cell proliferation. Xenograft tumor mice model was established by injection of MDA-MB-231. qRT-PCR and western blot were used to examine the expression of Nanog, Sox2 and OCT-4. Mammosphere forming assay was employed to evaluate mammosphere formation both in vivo and in vitro. Dual luciferase assay was utilized to verify the interaction between HMGB3 and hypoxia-inducible factor 1α (HIF1α). CD44+/CD24- was assessed with flow cytometry. Results: HMGB3 expression was higher significantly (p<0.05) in cancer cells compared to normal cells. HMGB3 overexpression significantly (p<0.05) enhanced and HMGB3 silence reduced cell proliferative mice compared to MCF10A and MDA-MB-231, respectively. HMGB3 overexpression enhanced and HMGB3 silence inhibited mammosphere formation. HMGB3 overexpression upregulated and HMGB3 silence downregulated Nanog, SOX2 and OCT-4 genes/proteins in MCF10A and MDA-MB-231 cells, respectively. HMGB3 silence reduced CD44+/CD24- levels in cancer cells. Silence of HMGB3 strengthened reductive effects of PTX on tumor sizes, iPSC biomarkers and mammosphere amounts in xenograft tumor mouse models. HMGB3 silence inhibited mammoshpere formation, cell proliferation and CD44+CD24- by interacting with HIF1α. Conclusion: HMGB3 silence could inhibit the cell proliferation in vitro and suppress tumor growth in vivo levels. The antitumor effects of HMGB3 silence were mediated by interacting with the HIF1α.

The Office Guidelines Applied to Practice program improves secondary prevention of heart disease in Federally Qualified Healthcare Centers.

UNLABELLED: The burden of cardiovascular disease (CVD) among minority and low-income populations is well documented. This study aimed to assess the impact of patient activation and shared decision-making (SDM) on medication use through the Office-Guidelines Applied to Practice (Office-GAP) intervention in Federally Qualified Healthcare Centers (FQHCs). Patients (243) with diabetes and CHD participated in Office-GAP between October 2010 and March 2014. Two-site (FQHCs) intervention/control design. Office-GAP integrates health literacy, communication skills education for patients and physicians, decision support tools, and SDM into routine care. MAIN MEASURES: 1) implementation rates, 2) medication use at baseline, 3, 6, and 12 months, and 3) predictors of medication use. Logistic regression with propensity scoring assessed impact on medication use. Intervention arm had 120 and control arm had 123 patients. We found that program elements were consistently used. Compared to control, the Office-GAP program significantly improved medications use from baseline: ACEIs or ARBs at 3 months (OR 1.88, 95% CI = 1.07; 3.30, p < 0.03), 6 months (OR 2.68, 95% CI = 1.58;4.54; p < 0.01); statin at 3 months (OR 2.00, 95% CI = 0.1.22; 3.27; p < 0.05), 6 months (OR 3.05, 95% CI = 1.72; 5.43; p < 0.01), Aspirin and/or clopidogrel at 3 months OR 1.59, 95% CI = 1.02, 2.48; p < 0.05), 6 months (OR 3.67, 95% CI = 1.67; 8.08; p < 0.01). Global medication adherence was predicted only by Office-GAP intervention presence and hypertension. Office-GAP resulted in increased use of guideline-based medications for secondary CVD prevention in underserved populations. The Office-GAP program could serve as a model for implementing guideline-based care for other chronic diseases.

Blood Pressure Control in Hypertensive Patients in Federally Qualified Health Centers: Impact of Shared Decision Making in the Office-GAP Program.

Background: Hypertension (HTN) in people with diabetes doubles the risk of cardiovascular disease. Prior patient activation studies largely show improved communication but little impact on behavior or health outcomes. We sought to 1) assess the impact of Office-Based Guidelines Applied to Practice (Office-GAP) Program on blood pressure (BP) control; 2) determine the rate and predictors of BP control in patients with HTN and/or diabetes mellitus (DM) in federally qualified health centers. Methods: Sample: Patients with coronary heart disease (CHD) and/or DM with history of HTN; analyzed patients with DM and HTN compared to HTN without DM. INTERVENTION: Office-GAP included physician training, patient activation, and an Office-GAP decision checklist. Two-site intervention/control design; data collection at baseline and after 3, 6, and 12 months. Logistic regression with propensity scoring assessed impact on BP control over time. Results: Of 243 patients, HTN was present in 75% at baseline; 32% had BP controlled. Consistent trend showed Office-GAP slightly improved the rate of BP control across time, while the control arm showed a nonsignificant decrease in the rate of BP control across time, compared to baseline. BP improved at 6 months at the intervention site compared to control site (odds ratio = 2.92; 95% confidence interval = 1.11-7.69). Conclusion: BP control was better at the intervention site compared to the control site at 6 months. Office-GAP shows promise to implement guidelines-based patient-centered care that improves BP.

Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure.

The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction.

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)(3) to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

Aryl to aryl palladium migration in the Heck and Suzuki coupling of o-halobiaryls.

A novel 1,4-palladium migration between the o- and o'-positions of biaryls has been observed in organopalladium intermediates derived from o-halobiaryls. The organopalladium intermediates generated by this migration have been trapped either by a Heck reaction employing ethyl acrylate or by Suzuki cross-coupling using arylboronic acids. This palladium migration can be activated or deactivated by choosing the appropriate reaction conditions. Chemical and computational evidence supports the presence of an equilibrium that correlates with the C-H acidity of the available arene positions.

Total synthesis of (+/-)-bipinnatin J.

[reaction: see text]. The total synthesis of (+/-)-bipinnatin J was achieved through a concise route that features the use of a silver ion promoted S(N)1-type gamma-alkylation of a siloxyfuran and a diastereoselective Cr(II)-mediated macrocyclization to provide bipinnatin J (1), wherein the remote furanone stereocenter at C10 induced the relative stereochemistry of the two additional stereocenters.

Enantiomeric separation of furan derivatives and fused polycycles by cyclodextrin-modified micellar capillary electrophoresis.

The enantiomeric separations of highly hydrophobic furan derivatives and polycycles were performed and optimized using CD-modified micellar CE. The most effective chiral selector for the enantiomeric separation of these analytes was hydroxypropyl-gamma-CD. The effects of CD and SDS concentration and organic modifier were examined in order to optimize the separation conditions. The ratio of CD to surfactant concentration affected the enantiomeric separation significantly, with increases in the derivatized CD concentration generally enhancing resolution. Addition of an organic solvent modifier to the run buffer served to increase the analytes' solubility and enhance the separation efficiency. A highly acidic pH was necessary to effectively suppress the EOF when operating in the reverse polarity mode.

Synthesis of fused polycycles by 1,4-palladium migration chemistry.

Novel palladium migration/arylation methodology for the synthesis of complex fused polycycles has been developed, in which one or more sequential Pd-catalyzed intramolecular migration processes involving C-H activation are employed. The chemistry works best with electron-rich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution.

Pd-catalyzed alkyl to aryl migration and cyclization: an efficient synthesis of fused polycycles via multiple C-H activation.

A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction providing a very efficient way to synthesize fused ring systems.

Synthesis of substituted naphthalenes and carbazoles by the palladium-catalyzed annulation of internal alkynes.

An efficient synthesis of highly substituted naphthalenes has been developed by the palladium-catalyzed annulation of a variety of internal alkynes, in which two new carbon-carbon bonds are formed in a single step under relatively mild reaction conditions. This method has also been used to synthesize carbazoles, although a higher reaction temperature is necessary. The process involves arylpalladation of the alkyne, followed by intramolecular Heck olefination and double-bond isomerization. This method accommodates a variety of functional groups and affords the anticipated highly substituted naphthalenes and carbazoles in good to excellent yields.

1,4-palladium migration via C-H activation, followed by arylation: synthesis of fused polycycles.

A novel palladium migration/arylation methodology for the synthesis of complex fused polycycles has been developed, in which one or more sequential Pd-catalyzed intramolecular migration processes involving C-H activation are employed. The chemistry works best with electron-rich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution.

Synthesis of 4-(1-alkenyl)isoquinolines by palladium(II)-catalyzed cyclization/olefination.

A variety of 4-(1-alkenyl)-3-arylisoquinolines have been prepared in moderate to excellent yields by the Pd(II)-catalyzed cyclization of 2-(1-alkynyl)arylaldimines in the presence of various alkenes. The introduction of an o-methoxy group on the arylaldimine promotes the Pd-catalyzed cyclization and stabilizes the resulting Pd(II) intermediate, improving the yields of the isoquinoline products. Ketone-containing isoquinolines 36 and 49-51 have also been prepared by this process when unsaturated alcohols are employed as the alkenes.

Synthesis of substituted naphthalenes by the palladium-catalyzed annulation of internal alkynes.

[reaction: see text] A variety of substituted naphthalenes have been prepared by the palladium-catalyzed carboannulation of internal alkynes. This method (1) forms two new carbon-carbon bonds in a single step, (2) accommodates a variety of functional groups, and (3) affords excellent yields of highly substituted naphthalenes.

Synthesis of substituted isoquinolines by electrophilic cyclization of iminoalkynes.

The tert-butylimines of o-(1-alkynyl)benzaldehydes and analogous pyridinecarbaldehydes have been cyclized under very mild reaction conditions in the presence of I(2), ICl, PhSeCl, PhSCl, and p-O(2)NC(6)H(4)SCl to give the corresponding halogen-, selenium-, and sulfur-containing disubstituted isoquinolines and naphthyridines, respectively. This methodology accommodates a variety of iminoalkynes and affords the anticipated heterocycles in moderate to excellent yields. Monosubstituted isoquinolines and naphthyridines have been synthesized by the metal-catalyzed ring closure of these same iminoalkynes. The silver-catalyzed ring closure is highly effective in cyclizing aryl-, alkenyl-, and alkyl-substituted iminoalkynes at 50 degrees C.