Dominant Gene Expression Profiles Define Adenoid Cystic Carcinoma (ACC) from Different Tissues: Validation of a Gene Signature Classifier for Poor Survival in Salivary Gland ACC.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant 'ACC phenotype'. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.

Can Essential Oils Provide an Alternative Adjuvant Therapy for COVID-19 Infections and Pain Management at the Same Time?

The active compounds from essential oils have been an important asset in treating different diseases for many centuries. Nowadays, there are various available formulations used as food supplements to stimulate the immune system. In light of the current pandemic and the large amount of fake news circulating the internet, it is important to analyze which of the active compounds from essential oils can be successfully used in the treatment of COVID-19 infections. We analyzed the current literature on the effects of essential oils against the new SARS-CoV-2 virus to gain a better understanding of the underlying mechanisms of these compounds and establish their possible antiviral efficacy. The available studies have highlighted the antiviral potential of active compounds from essential oils, indicating that they could be used as adjuvants in treating various viral infections, including COVID-19, leading to a milder course of the disease, and improving patients' outcomes. At the same time, these compounds relieve pain and lift the mood in comorbid patients suffering from opioid addiction. Essential oils might be useful as adjuvant tools, not only against SARS-CoV-2 but also for a subset of especially vulnerable patients affected with both COVID-19 and opioid addiction. However, randomized clinical trials are needed to determine their efficacy and develop standardized high-quality preparations that can be safely administered to the general population.

Natural medicine HLXL targets multiple pathways of amyloid-mediated neuroinflammation and immune response in treating alzheimer's disease.

BACKGROUND: Based on the complex pathology of AD, a single chemical approach may not be sufficient to deal simultaneously with multiple pathways of amyloid-tau neuroinflammation. A polydrug approach which contains multiple bioactive components targeting multiple pathways in AD would be more appropriate. Here we focused on a Chinese medicine (HLXL), which contains 56 bioactive natural products identified in 11 medicinal plants and displays potent anti-inflammatory and immuno-modulatory activity. HYPOTHESIS/PURPOSE: We investigated the neuroimmune and neuroinflammation mechanisms by which HLXL may attenuate AD neuropathology. Specifically, we investigated the effects of HLXL on the neuropathology of AD using both transgenic mouse models as well as microglial cell-based models. STUDY DESIGN: The 5XFAD transgenic animals and microglial cell models were respectively treated with HLXL and Aß42, and/or lipopolysaccharide (LPS), and then analyzed focusing on microglia mediated Aß uptake and clearance, as well as pathway changes. METHODS: We showed that HLXL significantly reduced amyloid neuropathology by upregulation of microglia-mediated phagocytosis of Aß both in vivo and in vitro. HLXL displayed multi-modal mechanisms regulating pathways of phagocytosis and energy metabolism. RESULTS: Our results may not only open a new avenue to support pharmacologic modulation of neuroinflammation and the neuroimmune system for AD intervention, but also identify HLXL as a promising natural medicine for AD. CONCLUSION: It is conceivable that the traditional wisdom of natural medicine in combination with modern science and technology would be the best strategy in developing effective therapeutics for AD.

Metastasectomy for Stage IVA Colon Cancer: Does the Type of Treating Institution Make a Difference?

Treatment of metastatic colon cancer has evolved over time. More evidence has been emerging in recent years supporting metastasectomy in selected patients. We sought to elucidate whether the type of institution-community, comprehensive community, academic/research, and integrated cancer network-would have an effect on patient outcome, specifically those colon cancer patients with isolated liver metastasis. This retrospective cohort study queried the National Cancer Database (NCDB) from 2010 to 2014 for patients who were 18 years of age or older with stage IVA colon cancer with isolated liver metastasis. We then performed uni- and multivariate analyses comparing patients based on such factors as age, tumor characteristics, primary tumor location, rate of chemotherapy, and type of treating institution. Patients who came from regions of higher income, receiving chemotherapy, and presenting to an academic/research hospital were more likely to undergo metastasectomy. Median survival was longest at academic/community hospitals at 22.4 months, 6 to 7 months longer than the other three types of institutions. Factors positively affecting survival included receiving chemotherapy, presenting to an academic/research institution, and undergoing metastasectomy, all at P < .05. In our study, the rate of metastasectomy was more than double at academic/research institutions for those with stage IVA colon cancer with isolated liver metastasis. Prior studies have quoted a mere 4.1% synchronous colon resection and metastasectomy. Our findings suggest that we should maintain multidisciplinary approach to this complex disease process and that perhaps it is time for us to consider regionalization of care in treating metastatic colon cancer.

Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era.

Since 2004, multiple blockbuster drugs have been approved for men with metastatic prostate cancer. Nevertheless, it has been reported that no improvement in survival was observed between 2004 and 2009. Herein, we have analyzed the SEER database to assess the survival outcome of metastatic prostate cancer patients since 2000. The results demonstrated that there was an improvement in both overall and prostate cancer-specific survival for 4 months among men diagnosed with metastatic prostate cancer from 2010 to 2016 when compared to those in the pre-2010 period. Interestingly, this survival benefit was limited to patients with bone and visceral metastasis (M1b and M1c stages). Collectively, our observation suggests that despite the new treatment agents such as second-line antiandrogen therapies introduced in the modern era, the improvement in survival of metastatic prostate cancer patients has been surprisingly small.

Cancer Pain Syndromes.

Pain from cancer can present in a multitude of ways. In this chapter, we will identify the types of cancer pain and their etiologies. Following this, we will explore how cancer pain can present as somatic pain, visceral pain, and neuropathic pain. We will explore the aspects of the history and physical examination that point to specific diagnoses of pain and how to appropriately treat each diagnosis appropriately. Finally, we will touch upon a phenomenon known as opioid neurotoxicity.

Role of Levo-tetrahydropalmatine and its metabolites for management of chronic pain and opioid use disorders.

BACKGROUND: Opioids have been prescribed to reduce suffering from pain and to enhance quality of life. Due to the addictive potential and the lack of other effective alternatives to treat severe acute and chronic pains, opioids remain a serious public health issue. While, opioids directly influence the drug-seeking behavior, tolerance and withdrawal processes, through neuroadaptation, the brain's endogenous opioid system also adapts in the presence of chronic pain and could contribute to the difficulty of treatment. Despite the seemingly obvious interaction between the presence of pain and opioid-abuse, little is known about the underlying mechanisms in the brain. PURPOSE: To review the current understanding of the interaction mechanisms of neurotransmitter circuitries in pain modulation and reward in the brain and the effects of L-tetrahydropalmatine (L-THP) and its metabolites in pain management and opioid use disorder and gain a better insight on the pharmacological profile and in vivo effects of L-THP and its metabolites. METHOD: A detailed literature search on available (preclinical and clinical) studies about the effects of L-THP and its metabolites against drug addiction and chronic pain has been performed. The data was collected using various search engines such as PubMed, ScienceDirect, Google scholar and articles in English up to December 2020 were included in this review. RESULTS: L-THP and its metabolites demonstrated analgesic and anti-addiction effects. Due to their dual pharmacological properties (D1 partial agonist and D2 antagonist) these compounds could be used as molecular tools to provide a better understanding of the interactions between pain and addiction. CONCLUSION: The available data confirms the potential of L-THP and its metabolites to treat both chronic pain and drug addiction. However, further clinical trials are needed to establish safety and efficacy.

Can eastern wisdom resolve western epidemics? Traditional Chinese medicine therapies and the opioid crisis.

The widespread use of opioids to treat chronic pain led to a nation-wide crisis in the United States. Tens of thousands of deaths annually occur mainly due to respiratory depression, the most dangerous side effect of opioids. Non-opioid drugs and non-pharmacological treatments without addictive potential are urgently required. Traditional Chinese medicine (TCM) is based on a completely different medical theory than academic Western medicine. The scientific basis of acupuncture and herbal treatments as main TCM practices has been considerably improved during the past two decades, and large meta-analyses with thousands of patients provide evidence for their efficacy. Furthermore, opinion leaders in the United States favor non-pharmacological techniques including TCM for pain management to fight the opioid crisis. We advocate TCM as therapeutic option without addictive potential and without life-threatening side effects (e.g., respiratory depression) to treat chronic pain patients suffering from opioid misuse. The evidence suggests that: (1) opioid misuse cannot be satisfactorily managed with standard medication; (2) opinion leaders in the United States favor to consider non-opioid and non-pharmacological treatment strategies including those from TCM to treat acute and chronic pain conditions; (3) large meta-analyses provide scientific evidence for the clinical activity of acupuncture and herbal TCM remedies in the treatment of chronic pain. Future clinical trials should demonstrate the safety of TCM treatments if combined with Western medical practices to exclude negative interactions between both modalities.

Health(care) in the Crisis: Reflections in Science and Society on Opioid Addiction.

Opioid abuse and misuse have led to an epidemic which is currently spreading worldwide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current rather unsystematic approaches to tackle this health problem are not effective. This review suggests that fighting the opioid epidemic requires a structured public health approach. Therefore, it is important to consider not only scientific and biomedical perspectives, but societal implications and the lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context of chronic pain as well as post-surgery treatments, as the entrance of opioids in people's lives. Linking pharmaceutical biology to narrative analysis is essential to understand the modulations of the usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient narratives can be an important resource in understanding the complexity of opioid abuse and addiction. In particular, the relationship between chronic pain and social inequality must be considered. The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched understanding can lead to more precise strategies of prevention or treatment of opioid abuse.

Traditional Chinese herbal medicine at the forefront battle against COVID-19: Clinical experience and scientific basis.

BACKGROUND: Throughout the 5000-year history of China, more than 300 epidemics were recorded. Traditional Chinese herbal medicine (TCM) has been used effectively to combat each of these epidemics' infections, and saved many lives. To date, there are hundreds of herbal TCM formulae developed for the purpose of prevention and treatment during epidemic infections. When COVID-19 ravaged the Wuhan district in China in early January 2020, without a deep understanding about the nature of COVID-19, patients admitted to the TCM Hospital in Wuhan were immediately treated with TCM and reported later with >90% efficacy. APPROACH: We conducted conduct a systematic survey of various TCM herbal preparations used in Wuhan and to review their efficacy, according to the published clinical data; and, secondly, to find the most popular herbs used in these preparations and look into the opportunity of future research in the isolation and identification of bioactive natural products for fighting COVID-19. RESULTS: Although bioactive natural products in these herbal preparations may have direct antiviral activities, TCM employed for fighting epidemic infections was primarily based on the TCM theory of restoring the balance of the human immune system, thereby defeating the viral infection indirectly. In addition, certain TCM teachings relevant to the meridian system deserve better attention. For instance, many TCM herbal preparations target the lung meridian, which connects the lung and large intestine. This interconnection between the lung, including the upper respiratory system, and the intestine, may explain why certain TCM formulae showed excellent relief of lung congestion and diarrhea, two characteristics of COVID-19 infection. CONCLUSION: There is good reason for us to learn from ancient wisdom and accumulated clinical experience, in combination with cutting edge science and technologies, to fight with the devastating COVID-19 pandemic now and emerging new coronaviruses in the future.

RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression.

DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3' untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1-E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression. SIGNIFICANCE: These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/315/F1.large.jpg.

Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma.

Acinic cell carcinoma (AcCC) is a morphologically distinctive salivary gland malignancy often associated with chromosome rearrangements leading to overexpression of the NR4A3 transcription factor. However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 archived AcCC samples revealed fusion reads arising from recurrent t(4;9), t(9;12), t(8;9) or t(2;4) chromosomal translocations, which positioned highly active enhancers adjacent to the promoter of the NR4A3 gene or the closely related NR4A2 gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both NR4A3 and MSANTD3. A poor survival subset of the tumors with high-grade transformation expressed NR4A3 and POMC as well as MYB, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of NR4A3 and MYB showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that NR4A3 and NR4A2 are the main driver genes of AcCC and suggest that concurrent overexpression of NR4A3 and MYB defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome.

Robotic Versus Laparoscopic Gastrectomy for Gastric Adenocarcinoma: Propensity-Matched Analysis.

Background. We compared the outcomes of laparoscopic-assisted (LA) and robotic-assisted (RA) gastrectomies performed for gastric adenocarcinoma in the National Cancer Database. Methods. The National Cancer Database was queried for patients 18 years old with stages I to III gastric adenocarcinoma who underwent LA or RA gastrectomy. Propensity matching was performed between the 2 groups with regard to clinical staging, adjuvant treatment, demographics, and the extent of surgery. Results. A cohort of 1893 (1262 = LA, 631 = RA) patients was identified in a 2:1 propensity matching. The groups were well matched. The rate of negative margin as well as 30- and 90-day mortality were similar between the 2 cohorts. Long-term survival was similar between the 2 groups (median survival 49.2 months in LA vs 56.2 months for RA, P = .405). However, the average number of lymph nodes (LNs) sampled was significantly higher in the RA group compared with the LA group (19.6 vs 17.4, P < .001). Similarly, the percentage of surgeries in which ≥15 LNs were sampled was also greater in the RA group compared with the LA group (63.9% vs 57.6%, P = .010). On multivariable analysis, having 15 LNs or more examined was associated with better survival (hazard ratio = 0.72, 95% confidence interval = 0.60-0.87, P < .001). Advanced age, nodal positivity, and advanced clinical stages were significantly associated with worse survival. Conclusions. RA gastrectomy may allow a greater harvest of LNs, and thus more accurate staging, without increasing short-term adverse outcomes compared with LA gastrectomy. Short-term and long-term outcomes in this well-matched cohort appear comparable for both approaches.

Implications of Prolonged Time to Pancreaticoduodenectomy After Neoadjuvant Chemoradiation.

BACKGROUND: For patients with pancreatic adenocarcinoma (PA), the optimal time interval between neoadjuvant chemoradiation (CR) to surgical resection has not been well established. METHODS: The National Cancer Database from 2006 to 2014 was queried for patients ≥18 y old diagnosed with PA who received neoadjuvant CR. Survival and short-term outcomes were compared between patients who had pancreaticoduodenectomy ≤12 wk and >12 wk after completion of CR. RESULTS: 1610 patients met selection criteria. Average radiation to surgery (RS) interval was 58.2 ± 39.5 d. 1419 patients had RS interval ≤12 wk (mean 47.4 d) and 191 had RS interval >12 wk (mean 138.8 d). Demographics, CA 19-9 levels, types of chemotherapy and radiation dosage were similar between the two groups. There were more patients with clinical stage III cancers in the >12 wk group than in the ≤12 wk group (33.5% versus 14%). Short-term outcomes were similar between the two groups. However, a long-term survival benefit was observed in the >12 wk group (median 25.8 versus 30.2 mo P = 0.049). An interval >12 wk was associated with significantly prolonged survival on multivariate analysis (HR: 0.80, 95% CI: 0.65-0.99; P = 0.042). Higher clinical stage and positive surgical margins were independently associated with worse survival. CONCLUSIONS: Surgical resection beyond 12 wk after CR for PA did not worsen short-term outcomes. Waiting may contribute to better patient selection, especially those with locally advanced tumors. In the absence of progressive disease, patients need to be continuously evaluated for surgical resection after CR.

Combining the wisdoms of traditional medicine with cutting-edge science and technology at the forefront of medical sciences.

BACKGROUND: A central topic is to bring traditional medicine to a new horizon by integrating the latest advances in genomic, metabolomic, and system biological approaches, in order to re-examine the wisdom and knowledge of traditional Chinese medicine (TCM) and other traditional medicines. PURPOSE: A new consortium has been formed at a conference of the Harvard Medical School, Boston, on October 29-30, 2018. The main goal was to build a collaborative platform for the scientific investigation of traditional medicine with cutting edge sciences and technologies at the forefront of biomedicine. RESULTS: Traditional medicines are largely experience-based, but the scientific basis is largely non-satisfactory. Therefore, the transformation from experience-based to evidence-based medicine would be an important step forward. The consortium covers three main fields: TCM diagnostics, acupuncture and TCM pharmacology. Diseases occur because of regulatory imbalances of holistic physiological display and genetic information/expression related to systems biology and energy consumption/release (e.g. cold and hot) within body. As organs are interconnected by meridians, affecting the meridians by acupuncture and medicinal herbs restores healthy organ function and body balance. There are two concepts in herbal medicine: The traditional way is based on complex herbal mixtures. The second concept is related to Western pharmacological drug development including the isolation of bioactive phytochemicals, which are subjected to preclinical and clinical investigations. CONCLUSION: Development of collaborative scientific project to integrate the best of both worlds - Western and Eastern medicine into a "One World Integrative Medicine" for the sake of patients worldwide.

Connecting Solution-Phase to Single-Molecule Properties of Ni(Salophen).

We present a strong correlation of the Ni(salophen) structure and properties measured in single-molecule vs bulk quantities and in ultra high vacuum vs solution phase. Under a scanning tunneling microscope (STM), Ni(salophen) forms a self-assembled monolayer (SAM) on Au(111) at 23 °C with molecular structure identical to that of the X-ray crystallographic measurement. The HOMO and LUMO levels are determined using elastic tunneling spectroscopy at the single-molecule level with confirmation by monolayer-quantity ultraviolet photoelectron spectroscopy (UPS) and by cyclic voltammetry (CV) measurements. The STM-determined HOMO-LUMO gap of 3.28 eV and (HOMO-1)-HOMO gap of 0.36 eV form a new foundation for the selection of hybrid functionals with a simple basis set to be effective in accurately calculating single-molecule Ni(salophen) frontier MO levels. Our results suggest that microscopy-based experiments on a surface, along with free-molecule gas-phase calculations, can provide useful insights into the physical properties of metal(salen) complexes, especially when such direct measurements are not available in solution.

Trends and Outcomes of Synchronous Resection of Colorectal Metastasis in the Modern Era-Analysis of Targeted Hepatic NSQIP Database.

BACKGROUND: Previous studies using the NSQIP database to study hepatectomies lacked hepatic specific variables and outcomes. We used the targeted NSQIP hepatectomy database to examine the nationwide trend and the safety profile of synchronous liver and colorectal resection compared with hepatectomy alone for colorectal liver metastasis. METHODS: The targeted NSQIP hepatectomy database from 2014 was used to study patients who underwent hepatectomy for diagnosis of adenocarcinoma of the colon and rectum. RESULTS: Of the 3064 hepatic resections in the database, 1138 cases were performed for colorectal metastasis. Of these, 1040 were liver-alone surgery and 98 were synchronous liver and colorectal resection. Most (58.7%) patients received neoadjuvant therapy. The rate of neoadjuvant therapy, intraoperative ablation, biliary reconstruction, and the use of minimally invasive technique were similar between the two groups. The overall 30-d mortality in this cohort was low (1.1%). While the mortality rate in the synchronous group was similar to liver-only group (3.1% versus 0.9%, P = 0.077). The rate of liver failure (3.3% versus 4.1%, P = 0.722) and biliary leak (5.3% versus 9.6%, P = 0.084) were similar between the two groups. However, the rate of major complications was higher on multivariable analyses (25.5% versus 12.1%, OR 2.5, 95% CI 1.5-4.1, P < 0.001) for the synchronous group. CONCLUSIONS: Hepatic resection for colorectal metastasis in the modern era has low short-term mortality. While synchronous resection was associated with a higher incidence of major complications, liver-specific complications did not increase with synchronous resection.

Racial disparities in breast cancer persist despite early detection: analysis of treatment of stage 1 breast cancer and effect of insurance status on disparities.

PURPOSE: Prior research demonstrates racial disparities in breast cancer treatment. Disparities are commonly attributed to more advanced stage at presentation or aggressive tumor biology. We seek to evaluate if racial disparities persist in the treatment of stage 1 breast cancer patients who by definition are not delayed in presentation. METHODS: We selected stage 1 breast cases in the National Cancer Data Base. Patients were divided into two cohorts based on race and included White and Black patients. We also performed a subgroup analysis of patients with private insurance for comparison to determine if private insurance diminished the racial disparities noted. We analyzed differences in time to treatments by race. RESULTS: Our analysis included 546,351 patients of which 494,784 (90.6%) were White non-Hispanic and 51,567 (9.4%) were Black non-Hispanic. Black women had significantly longer times to first treatment (35.5 days vs 28.1 days), surgery (36.6 days vs 28.8 days), chemotherapy (88.1 days vs 75.4 days), radiation (131.3 days vs 99.1 days), and endocrine therapy (152.1 days vs 126.5 days) than White women. When patients with private insurance were analyzed the difference in time to surgery decreased by 1.2 days but racial differences remained statistically significant. CONCLUSIONS: Despite selecting for early-stage breast cancer, racial disparities between White and Black women in time to all forms of breast cancer treatment persist. These disparities while likely not oncologically significant do suggest institutional barriers for obtaining care faced by women of color which may not be addressed with improving access to mammography alone.