From Diversity, Equity, and Inclusion to an Antiracism Strategic Plan: An Academic Department of Psychiatry's Journey.

The efforts of an academic psychiatry department to embark on an antiracism strategic planning process are outlined, including the establishment of an antiracism task force charged with the development of an antiracism strategic plan. The initial process of the task force is described, recommendations are summarized, and future directions are outlined.

Afatinib triggers a Ni2+ -resistant Ca2+ influx pathway in A549 non-small cell lung cancer cells.

Afatinib is used to treat non-small cell lung cancer cells (NSCLC), and its mechanism involves irreversible inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase. In this study, we examined if afatinib had cytotoxic action against NSCLC other than inhibition of tyrosine kinase. Afatinib (1-30 µM) caused apoptotic death in A549 NSCLC in a concentration-dependent manner. Afatinib triggered Ca2+ influx without causing Ca2+ release, and the Ca2+ influx was unaffected by sodium orthovanadate (SOV, an inhibitor of tyrosine phosphatase), suggesting that afatinib-triggered Ca2+ response was unrelated to its inhibition of tyrosine kinase. Addition of afatinib also promoted Mn2+ influx. Ca2+ influx triggered by afatinib was resistant to SKF96365 and ruthenium red (two general blockers of TRP channels) and, unexpectedly, Ni2+ (a non-specific Ca2+ channel blocker). Afatinib caused an increase in mitochondrial Ca2+ level, an initial mitochondrial hyperpolarization (4 h) and followed by mitochondrial potential collapse (24-48 h). Afatinib-induced cell death was slightly but significantly alleviated in low extracellular Ca2+ condition or under pharmacological block of mitochondrial permeability transition pore (MPTP) opening by cyclosporin A. Therefore, in addition to tyrosine kinase inhibition as a major anti-cancer mechanism of afatinib, stimulation of an atypical Ca2+ influx pathway, mitochondrial Ca2+ overload, and potential collapse in part contribute to afatinib-induced cell death.

Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers.

The current clinical management model of HER2-positive breast cancers is commonly based on guidelines, which in turn are based on the design and outcome of clinical trials. While this model is useful to most practicing clinicians, the treatment outcome of individual patient is not certain at the start of treatment. As the understanding of the translational research of carcinogenesis and the related changes in cancer genetics and tumor microenvironment during treatment is critical in the selection of right choice of treatment to maximize the successful clinical outcome for the patient, this review article intends to discuss the latest developments in the genetic and molecular mechanisms of cancer progression and treatment resistance, and how they influence the planning of the treatment strategies of HER2-positive breast cancers.

Perceived Importance of Breast Cancer Risk Factors: A Survey on 386 Physicians in China.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience.  This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.

PURPOSE: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). PATIENTS AND METHODS: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods. RESULTS: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI. CONCLUSIONS: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib.

PURPOSE: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

A basal level of γ-linolenic acid depletes Ca2+ stores and induces endoplasmic reticulum and oxidative stresses to cause death of breast cancer BT-474 cells.

Gamma-linolenic acid (GLA), a natural fatty acid obtained from oils of various vegetables and seeds, has been demonstrated as an anticancer agent. In this work, we investigated the anticancer effects of GLA on breast cancer BT-474 cells. GLA at 30 µM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death. GLA caused an elevation in mitochondrial Ca2+ level and a decrease in mitochondrial membrane potential. GLA treatment depleted cyclopiazonic acid (CPA)-sensitive Ca2+ store and triggered substantial Ca2+ influx. Intracellular Ca2+ release triggered by GLA was suppressed by 3 µM xestospongin C (XeC, IP3 receptor-channel blocker) and 100 µM ryanodine (ryanodine receptor-channel blocker), suggesting that the Ca2+ release was via IP3 receptor-channel and ryanodine receptor-channel. Increased expressions of p-eIF2α and CHOP were observed in GLA-treated cells, suggesting GLA-treated cells had increased expressions of p-eIF2α and CHOP, which suggest endoplasmic reticulum (ER) stress. In addition, GLA elicited increased production of reactive oxygen species. Taken together, our results suggest a basal level of GLA induced apoptotic cell death by causing Ca2+ overload, mitochondrial dysfunction, Ca2+ store depletion, ER stress, and oxidative stress. This is the first report to show that GLA caused Ca2+ store depletion and ER stress. GLA-induced Ca2+ store depletion resulted from opening of IP3 receptor-channel and ryanodine receptor-channel.

Lipotoxicity in human lung alveolar type 2 A549 cells: Mechanisms and protection by tannic acid.

Palmitic acid (PA) is a saturated free fatty acid which, when being excessive, accounts for lipotoxicity. Using human lung A549 cells as a model for lung alveolar type 2 epithelial cells, we found that challenge of A549 cells with PA resulted in apoptotic cell death, as reflected by positive annexin V and PI staining, and also appearance of cleaved caspase-3. PA treatment also caused depletion of intracellular Ca2+ store, endoplasmic reticulum (ER) stress, and oxidative stress. Tannic acid (TA), a polyphenol present in wines and many beverages, alleviated PA-induced ER stress, oxidative stress and apoptotic death. Thus, our results suggest PA lipotoxicity in lung alveolar type 2 epithelial cells could be protected by TA.

Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7).

BACKGROUND: This analysis evaluated patient-reported outcomes (PROs) to assess health-related quality of life (HRQoL) in the phase III MONALEESA-7 trial, which previously demonstrated improvements in progression-free survival (PFS) and overall survival (OS) with ribociclib (cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) compared with placebo + ET in pre- and perimenopausal patients with hormone-receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). METHODS: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire C30 (QLQ-C30) and the EQ-5D-5L were used to evaluate HRQoL. RESULTS: EORTC QLQ-C30 assessments were evaluable for 335 patients in the ribociclib arm and 337 patients in the placebo arm. Adherence rates at baseline and ⩾1 postbaseline time point were 90% and 83%, respectively. Patients treated with ribociclib + ET had a longer time to deterioration (TTD) ⩾ 10% in global HRQoL {hazard ratio (HR), 0.67 [95% confidence interval (CI), 0.52-0.86]}. TTD ⩾ 10% in global HRQoL was delayed in ribociclib-treated patients without versus with disease progression [HR, 0.31 (95% CI, 0.21-0.48)]. TTD ⩾ 10% in pain was longer with ribociclib + ET than with placebo + ET [HR, 0.65 (95% CI, 0.45-0.92)]. Patients who received a nonsteroidal aromatase inhibitor experienced similar benefits with ribociclib versus placebo in global HRQoL and pain. CONCLUSION: HRQoL was maintained longer in patients who received ribociclib + ET versus placebo + ET. These data, combined with previously reported improvements in PFS and OS, support a strong clinical benefit-to-risk ratio with ribociclib-based treatment in pre- and perimenopausal patients with HR+/HER2- ABC.

Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: phase II randomized, placebo-controlled study.

PURPOSE: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). METHODS: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. RESULTS: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). CONCLUSION: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.

Advances in EGFR/HER2-directed clinical research on breast cancer.

The discovery of the HER2 molecules has embarked a series of investigations on the efficacy and safety of different types of anti-HER2 therapies for treating breast cancer, with the clinical pathway requiring a more detailed, more precise, and more dynamics therapeutic approaches due to the heterogeneity of the disease. As the "do more" and "do less" approaches are becoming more important to personalize treatment for early HER2-positive breast cancer, recent advances aim at tackling the advanced stage of the disease by using novel therapeutic agents and combination strategies. There are also important points of consideration on prognosis and choice of therapies, including HER2 gene copy number, HER2 heterogeneity, tissue biomarkers, blood-based biomarkers, and HER2 mutation and its treatment. Altogether, these could potentially play a vital role in the journey of HER2-positive breast cancer patient to achieve greater survival benefit and potentially a cure for the disease.

Polyamine stimulation perturbs intracellular Ca2+ homeostasis and decreases viability of breast cancer BT474 cells.

Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells. Our data showed that spermine, spermidine, and putrescine decreased cell viability by apoptosis. These polyamines also elicited Ca2+ signals, but the latter were unlikely triggered via Ca2+-sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca2+ response composed of both Ca2+ release and Ca2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca2+ influx pore opened by spermine was Mn2+-impermeable, distinct from the CPA-triggered store-operated Ca2+ channel, which was Mn2+-permeable. Spermine cytotoxic effects were not due to oxidative stress, as spermine did not trigger reactive oxygen species formation. Our results therefore suggest that spermine acted on a putative polyamine receptor in BT474 cells, causing cytotoxicity by Ca2+ overload, Ca2+ store depletion, and ER stress.

The versatile Kv channels in the nervous system: actions beyond action potentials.

Voltage-gated K+ (Kv) channel opening repolarizes excitable cells by allowing K+ efflux. Over the last two decades, multiple Kv functions in the nervous system have been found to be unrelated to or beyond the immediate control of excitability, such as shaping action potential contours or regulation of inter-spike frequency. These functions include neuronal exocytosis and neurite formation, neuronal cell death, regulation of astrocyte Ca2+, glial cell and glioma proliferation. Some of these functions have been shown to be independent of K+ conduction, that is, they suggest the non-canonical functions of Kv channels. In this review, we focus on neuronal or glial plasmalemmal Kv channel functions which are unrelated to shaping action potentials or immediate control of excitability. Similar functions in other cell types will be discussed to some extent in appropriate contexts.

Intraneural granular cell tumor: Histologic spectrum and histogenetic implication.

Granular cell tumor (GCT), despite its putative neural origin, commonly occurs in extraneural sites; only six single case reports of intraneural GCT have been described. We report an unique case as the only one with motor dysfunction, the longest duration of symptoms, and largest tumor size with resultant muscle atrophy and fatty infiltration. Upon review of these cases, the striking feature of intraneural GCT lies in its histologic variety, ranging from benign GCT, through plexiform, hybrid GCT and perineurioma to malignant GCT, encompassing the full spectrum of extraneural GCT. As the immunophenotypes of schwannoma and GCT are not exactly identical, together with evidence from ultrastructural studies, the more reasonable and likely possibility is that GCT originates from undifferentiated mesenchymal cells acquiring partial schwannian differentiation. Such postulation by virtue of the widespread occurrence of mesenchymal cells in the soft tissue, better explains the topographic distribution of GCT in extraneural and intraneural location.

Training needs among nonmental health professionals working with service members: A qualitative investigation.

Though many service members will not directly seek mental health care due to stigma and other factors, they may interact with the healthcare system in other ways including contact with first responders, nurses and allied health care professionals. However, little attention has been spent in this regard on the educational needs of these professionals whose contact with service members and veterans may provide the opportunity to assist veterans in need with overcoming barriers to accessing mental health care. This qualitative study investigates the educational training needs of first responders and health care professionals in contact with military families and trauma survivors to determine whether, and what type, of additional training is needed. A sample of 42 first responders and health care professionals including emergency medical technicians, police officers, fire fighters, speech language pathologists, occupational therapists, physical therapists, and nurses, were recruited to participate in one of six focus groups. Sessions were audio-taped and transcribed verbatim. Data analysis was guided by a thematic analysis approach. Thematic analyses suggest there is a significant knowledge gap with unmet educational needs of these professionals such as information on the invisible wounds of war, military culture, and screening and referring patients who present symptoms falling outside professionals' scope of practice. Findings point to a need and desire for more robust education for first responders and health care providers around mental health concerns of military populations, including topics such as trauma, military culture, and screening tools. Efforts to develop curricula addressing these concerns are warranted.

Neratinib-based therapy in patients with metastatic HER2-positive breast cancer from Asia.

Aim: To evaluate the safety and efficacy of neratinib-based therapy in Asian patients with HER2-positive metastatic breast cancer (MBC). Patients & methods: We performed a pooled analysis of seven early-phase studies of neratinib given either as monotherapy or in combination with chemotherapeutic agents or trastuzumab in patients with advanced solid tumors. Results: A total of 793 patients with HER2-positive MBC were included in the efficacy analysis (Asia: 271 patients; other regions: 522 patients). The overall response rate in patients from Asia was 66.4% (180/271) and the median progression-free survival was 55.6 weeks. The most common adverse event in patients from Asia was diarrhea (all-grade: 96.3%; grade 3: 27.4%). Conclusion: Neratinib-based therapy is safe and effective in patients with HER2-positive MBC from Asia.

Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.

BACKGROUND: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival. METHODS: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87). CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).

Training community providers in evidence-based treatment for PTSD: Outcomes of a novel consultation program.

OBJECTIVE: Extensive research supports the use of prolonged exposure (PE) and cognitive processing therapy (CPT), for posttraumatic stress disorder (PTSD) in veterans and service members. PE and CPT have been disseminated nationally across the Department of Veterans Affairs (VA) facilities. Many service members and veterans receive care outside the VA where access to these gold standard psychotherapies can be limited. This paper presents a novel program developed to train community providers in the use of PE and CPT and their application to veterans with PTSD through the use of a medium-touch approach to consultation. METHOD: Four 2-day trainings (2 in PE, 2 in CPT) were delivered to a total of 170 participants over an 8-month period. A subset of approximately 10 providers per training (n = 42) received 6 months of weekly, group phone consultation following the 2-day training. All providers were assessed pre- and posttraining, as well as 3 and 6 months after their training. Outcomes for the training workshop alone and the training plus 6 months of consultation were compared. RESULTS: While participant knowledge, t = -22.57, p < .001 and comfort (χ² = 74.00, p < .001) with PE and CPT significantly increased immediately following the 2-day training, those who received consultation were more likely to implement (χ² = 20.88, p < .001) and either complete or be close to completing PE or CPT with patients (χ² = 20.57, p < .001) 6 months following training. CONCLUSIONS: Despite some limitations, these preliminary data support that consultation is an important component to include in PTSD therapy training and implementation in the community. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production.

ATP depletion induced by inhibiting glycolysis or mitochondrial ATP production has been demonstrated to cause cancer cell death. Whether ATP depletion can enhance the efficacy and potency of anti-cancer effects of herbal compounds is so far unknown. We examined the enhancing effect of ATP depletion on anti-cancer actions of tetrandrine (TET) in human lung carcinoma A549 cells. A 24-h incubation of A549 cells with tetrandrine caused a concentration-dependent cytotoxic effect (LC50 = 66.1 µM). Co-incubation with 20 mM 2-deoxyglucose (2-DG, glycolysis inhibitor) caused only a very slight enhancement of tetrandrine cytotoxicity. By contrast, inhibiting mitochondrial ATP production with oligomycin (10 µM, ATP synthase inhibitor) and FCCP (30 µM, uncoupling agent) (thus, oligo-FCCP) on its own caused only slight cell cytotoxicity but strongly potentiated tetrandrine cytotoxicity (tetrandrine LC50 = 15.6 µM). The stronger enhancing effect of oligo-FCCP than 2-DG on TET toxicity did not result from more severe overall ATP depletion, since both treatments caused a similar ATP level suppression. Neither oligo-FCCP nor 2-DG synergized with tetrandrine in decreasing mitochondrial membrane potential. TET on its own triggered reactive oxygen species (ROS) production, and oligo-FCCP, but not 2-DG, potentiated TET in causing ROS production. Taken together, our results suggest that inhibiting ATP production from mitochondria, but not from glycolysis, appears to be a very effective means in augmenting TET-triggered ROS production and hence toxicity in A549 cells.

Coronary artery myointimal dysplasia in patients with pheochromocytoma-possible causal relationship: pathophysiology and clinical implication with reference to Takotsubo cardiomyopathy and spontaneous coronary dissection.

Myocardial damage in catecholamine cardiomyopathy, characterized by patchy myocyte necrosis commonly with contraction band appearances, interstitial fibrosis, and varying degrees of inflammatory infiltrates, has been well documented. However, coronary vascular pathology has not been recognized. Autopsy of a 43-year-old housewife who died of acute apical anteroseptal myocardial infarction revealed the incidental finding of a left adrenal pheochromocytoma. The epicardial and intramyocardial median- and small-sized coronary arteries exhibited myointimal dysplasia in the form of fibroblastic proliferation in the intima and media, resulting in thickened dysplastic vessels with marked luminal narrowing, occasionally leading to near-total occlusion. The distal left anterior descending artery showed features of recanalization after prior embolic occlusion. The density and severity of vascular involvement revealed a decreasing gradient from apical to basal region, mainly affecting the left ventricle, but the proximal coronary arteries were minimally affected. Myointimal dysplasia was not seen in control cases of hypertensive heart, and despite its presence in hearts with hypertrophic cardiomyopathy, it lacked the distinctive pattern of distribution and the epicardial vessels are uninvolved. Myointimal dysplasia probably results from reactive fibroplasia in response to the vasoconstrictive effect of circulating or local neurosecretory catecholamine and appears crucial in the pathogenesis of various types of catecholamine cardiomyopathy, including Takotsubo or stress cardiomyopathy. Together with the direct catecholamine cardiotoxicity, they result in diffuse microscopic ischemic necrosis and fibrosis. Depending on the type of catecholamine overproduction and action, together with the characteristic anatomic distribution and density of the various types of adrenergic receptors in the ventricles, different regions of the heart are variously affected so that different patterns of ventricular dysfunction are produced, with the subsequent angiographic appearances ranging from apical through midventricular to basal ballooning. Additional complications from the myointimal dysplasia include spontaneous coronary dissection, acute myocardial infarction, and superimposed thrombus formation in the dysplastic vessels and dyskinetic ventricle, with the risk of further damage from embolic events.