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1.
Org Lett ; 22(2): 679-683, 2020 01 17.
Article in English | MEDLINE | ID: mdl-31904980

ABSTRACT

Piperazine-containing compounds serve as one of the most important classes of compounds throughout all fields of chemistry. Alas, current synthetic methods have fallen short of providing a general method for the synthesis of highly decorated piperazine fragments. Herein, we present a site-selective approach to the C-H functionalization of existing piperazine compounds using photoredox catalysis. This manifold relies on the predictable differentiation of electronically distinct nitrogen centers within the piperazine framework, granting access to novel C-alkylated variants of the starting piperazines.

2.
Pathol Res Pract ; 214(1): 76-79, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29254796

ABSTRACT

Evaluation of vulvar intraepithelial neoplasia (VIN) may be difficult due to overlapping histologic features seen in both usual (UVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). DVIN represents a diagnostic challenge; poor inter-observer agreement is well documented. P53 has been described as a potentially helpful adjunct in some cases; however, intricacies in its interpretation remain. This study evaluated 41 consecutive cases which consisted of 23 keratinizing dysplasias that were morphologically suggestive of DVIN and 18 UVINs. All cases were stained with p16 and p53. Our results revealed that 22 of 41 (54%) VINs showed novel accentuated wild type (WT) staining with non-linear basal staining for p53, including 12 (52%) cases histologically suggestive of DVIN and 10 (56%) described as UVIN. P16 was positive in 100% of the accentuated wild type cases, consistent with a diagnosis of UVIN. Positive p53 and negative p16 staining was seen in 4 (17%) cases histologically suggestive of DVIN. Of these, 75% progressed to carcinoma, whereas only 1 of 35 (3%) patients with UVIN progressed to carcinoma. In conclusion, DVIN is difficult to diagnose due to potential histologic overlap with UVIN, especially the warty, or keratinizing, subtype. Accentuated WT p53 in absence of concurrent p16 staining may lead to misdiagnosis of DVIN, especially in small biopsy samples. P16/p53 staining should be performed in tandem with strict adherence to patterns considered positive, as patients with UVIN have significantly less risk of progression.


Subject(s)
Tumor Suppressor Protein p53/metabolism , Vulvar Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Female , Humans , Immunohistochemistry/methods , Oligonucleotide Array Sequence Analysis/methods , Pathology, Molecular , Vulvar Neoplasms/pathology
3.
Science ; 358(6360): 218-223, 2017 10 13.
Article in English | MEDLINE | ID: mdl-29026042

ABSTRACT

Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.


Subject(s)
Adjuvants, Immunologic/chemical synthesis , Anti-HIV Agents/chemical synthesis , Bryostatins/chemical synthesis , HIV Infections/drug therapy , HIV-1/drug effects , Virus Latency/drug effects , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Bryostatins/chemistry , Bryostatins/pharmacology , Bryostatins/therapeutic use , Disease Eradication , Humans
4.
J Am Chem Soc ; 137(28): 9088-93, 2015 Jul 22.
Article in English | MEDLINE | ID: mdl-25961416

ABSTRACT

New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.


Subject(s)
Alkenes/chemistry , Anthracenes/chemical synthesis , Cycloaddition Reaction/methods , Ethane/analogs & derivatives , Fluorescent Dyes/chemical synthesis , Anthracenes/chemistry , Catalysis , Cycloaddition Reaction/economics , Ethane/chemistry , Fluorescent Dyes/chemistry , Indicators and Reagents/chemistry , Metals/chemistry
5.
Nat Chem ; 6(5): 448-52, 2014 May.
Article in English | MEDLINE | ID: mdl-24755598

ABSTRACT

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions--the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.


Subject(s)
Alkynes/chemical synthesis , Alkynes/chemistry , Cyclization , Molecular Structure
6.
J Anxiety Disord ; 28(1): 108-14, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23764125

ABSTRACT

This retrospective chart review evaluates the effectiveness of manualized cognitive processing therapy (CPT) protocols (individual CPT, CPT group only, and CPT group and individual combined) and manualized prolonged exposure (PE) therapy on veterans' posttraumatic stress disorder (PTSD) symptoms in one Veterans Health Administration (VHA) specialty clinic. A total of 517 charts were reviewed, and analyses included 178 charts for CPT and 85 charts for PE. Results demonstrated CPT and PE to significantly reduce PTSD Checklist (PCL) scores. However, PE was significantly more effective than CPT after controlling for variables of age, service era, and ethnicity. Additional findings included different outcomes among CPT formats, decreased treatment dropouts for older veterans, and no significant differences in outcome between Hispanic and White veterans. Study limitations and future research directions are discussed.


Subject(s)
Cognitive Behavioral Therapy/methods , Implosive Therapy/methods , Stress Disorders, Post-Traumatic/therapy , Veterans/psychology , Adult , Aged , Ambulatory Care Facilities , Female , Humans , Male , Middle Aged , Psychotherapy, Group , Retrospective Studies , Treatment Outcome , United States , United States Department of Veterans Affairs , Veterans/statistics & numerical data , Young Adult
7.
J Rehabil Res Dev ; 49(5): 703-15, 2012.
Article in English | MEDLINE | ID: mdl-23015581

ABSTRACT

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric diagnosis among veterans and has high comorbidity with other medical and psychiatric conditions. This article reviews the pharmacotherapy recommendations from the 2010 revised Department of Veterans Affairs/Department of Defense Clinical Practice Guideline (CPG) for PTSD and provides practical PTSD treatment recommendations for clinicians. While evidence-based, trauma-focused psychotherapy is the preferred treatment for PTSD, pharmacotherapy is also an important treatment option. First-line pharmacotherapy agents include selective serotonin reuptake inhibitors and the selective serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line agents have less evidence for their usefulness in PTSD and carry a potentially greater side effect burden. They include nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors. Prazosin is beneficial for nightmares. Benzodiazepines and antipsychotics, either as monotherapy or used adjunctively, are not recommended in the treatment of PTSD. Treating co-occurring disorders, such as major depressive disorder, substance use disorders, and traumatic brain injury, is essential in maximizing treatment outcomes in PTSD. The CPG provides evidence-based treatment recommendations for treating PTSD with and without such co-occurring disorders.


Subject(s)
Psychotropic Drugs/therapeutic use , Stress Disorders, Post-Traumatic/drug therapy , Veterans/psychology , Clinical Trials as Topic , Evidence-Based Medicine , Government Agencies , Humans , Practice Guidelines as Topic , Psychotropic Drugs/classification , Stress Disorders, Post-Traumatic/diagnosis , Treatment Outcome , United States , United States Department of Veterans Affairs
8.
Chem Commun (Camb) ; 48(65): 8102-4, 2012 Aug 21.
Article in English | MEDLINE | ID: mdl-22763579

ABSTRACT

The direct conversion of a polycyclic aromatic hydrocarbon bay region to a new, unsubstituted benzene ring by Diels-Alder cycloaddition of acetylene gas is reported for the first time. At 140 °C in dimethylformamide, under 1.8 atm pressure of acetylene gas, 7,14-dimesitylbisanthene is slowly converted to 7,14-dimesitylbenzo[ghi]bisanthene (21% conversion in 48 h).

9.
Mil Med ; 175(10): 719-24, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20968260

ABSTRACT

Trauma disclosure is the initial step toward healing trauma-related distress. This study used qualitative methods to better understand factors facilitating and inhibiting change in the disclosure process. Fifty-six veterans were interviewed about their disclosure experiences between August 2004 and 2005. Emerging themes and barriers to disclosure from 23 of these interviews are reported in this article. Barriers to trauma disclosure included lack of trust in the provider, fears about the potential negative consequences of disclosure, and trauma avoidance. Providers perceived as caring and communicating at the same level as the participants facilitated disclosure, whereas providers perceived as uncaring or disinterested inhibited disclosure. Veterans reported both positive and negative reactions to initial disclosure, but nearly all agreed that disclosure was worthwhile over the long-term. Improving patient-provider communications and creating settings that facilitate trauma disclosure may improve healing after trauma.


Subject(s)
Disclosure , Stress Disorders, Post-Traumatic/psychology , Veterans/psychology , Wounds and Injuries/psychology , Adult , Female , Humans , Male , Middle Aged , Physician-Patient Relations , United States , Wounds and Injuries/etiology , Young Adult
10.
Gen Hosp Psychiatry ; 30(2): 100-3, 2008.
Article in English | MEDLINE | ID: mdl-18291291

ABSTRACT

OBJECTIVE: The purpose of this study is to gain a better understanding of patients' trauma disclosure to health professionals. METHOD: A convenience sample of 173 veterans in outpatient treatment for posttraumatic stress disorder (PTSD) in the Veterans Health Administration completed surveys querying trauma history, reasons for trauma disclosure and perceived provider responses. RESULTS: For half of the participants, a healthcare provider was the first person to whom they disclosed. Reasons were primarily external, such as pressure from others. Although 72% were glad to disclose, 45% perceived at least one negative provider response. CONCLUSION: Patients disclose to a wide range of provider types and perceive varied responses. Providers' awareness of the need to be sensitive to trauma disclosure could facilitate treatment for PTSD.


Subject(s)
Self Disclosure , Veterans , Wounds and Injuries , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Health Personnel , Humans , Male , Middle Aged , Stress Disorders, Post-Traumatic , United States/epidemiology , Wounds and Injuries/classification , Wounds and Injuries/epidemiology
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