The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies.

STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.

Hipnoterapia para el logro de adecuados indicadores del parto en gestantes adolescentes con síntomas psicológicos derivados de la COVID-19 / Hypnotherapy for the achievement of appropriate indicators of the childbirth in pregnant adolescents with psychological symptoms derived from the COVID-19

Introducción: La adolescencia comprende entre los 10 y 19 años de edad, periodo donde el embarazo tiene mayor riesgo de complicaciones en la madre y el neonato. La COVID-19 incrementa la posibilidad de aparición de complicaciones psicológicas, que de no ser atendidas, inciden negativamente en el embarazo y el parto. En el presente estudio las pacientes fueron tratadas mediante hipnoterapia. Objetivo: Evaluar la efectividad del modelo hipnoterapéutico para el logro de adecuados indicadores del parto en adolescentes gestantes con síntomas psicológicos derivados de la COVID-19. Métodos: Se realizó un estudio de intervención hipnoterapéutica en 9 gestantes adolescentes con síntomas psicológicos derivados de la COVID - 19, ingresadas en el Hospital Nutricional Materno Este de Santiago de Cuba, desde abril hasta junio del 2020. Las pacientes tuvieron seguimiento hasta después del parto. Resultados: Se halló que 7 embarazadas (77,8 %) tuvieron parto eutócico y percibieron el dolor de este como mediano; en 66,7 % no hubo necesidad de usar analgésicos y 8 de ellas (88,9 %) no presentaron complicaciones. Además, todos los neonatos tuvieron un apgar normal. Conclusiones: El modelo hipnoterapéutico para el tratamiento de las gestantes adolescentes con síntomas psicológicos derivados de la COVID-19 logró mejorar indicadores del parto y otros parámetros asociados a este.

Introduction: The adolescence covers between the 10 and 19 years, period in which the pregnancy has higher risk of complications in the mother and the newborn. The COVID-19 increases the possibility of emergence of psychological complications that impact negatively in pregnancy and childbirth if they are not assisted. In this study the patients were treated by means of hypnotherapy. Objective: To evaluate the effectiveness of the hipnotherapeutic pattern for the achievement of appropriate indicators of childbirth in pregnant adolescents with psychological symptoms derived from the COVID-19. Methods: A study of hipnoterapeutic intervention was carried out in 9 pregnant adolescents with psychological symptoms derived from the COVID - 19, admitted to the Eastern Maternal Nutritional Hospital in Santiago de Cuba, from April to June, 2020. The patients had follow up until after the childbirth. Results: It was found that 7 pregnant women (77.8 %) had eutocic childbirth and perceived the pain as medium; in 66.7 % there was not necessity to use analgesic and 8 of them (88.9 %) didn't present complications. Also, all the newborns had a normal apgar. Conclusions: The hipnotherapeutic pattern for the treatment of pregnant adolescents with psychological symptoms derived from the COVID-19 was able to improve indicators of childbirth and other parameters associated with it.

"That's No Longer Tolerated": Policing Patients' Use of Non-opioid Substances in Methadone Maintenance Treatment.

The current overdose crisis in the United States emphasizes the importance of providing substance use treatment programs that are not only effective but tailored to meet the specific needs of the populations they serve. While Methadone Maintenance Treatment (MMT) is considered to be among the best strategies for reducing rates of opioid-involved overdose, its ability to attract and maintain patients may be hindered by a recent focus on policing the non-opioid substance use of people on the program. This paper uses interview data from treatment providers to examine how clinicians conceptualize and organize MMT in regards to patients' use of non-opioid drugs. Responses demonstrate that some treatment providers are increasingly monitoring their patients' use of non-opioid substances and punishing them for infractions, up to and including discharge from treatment. This approach will likely result in increasing rates of patient dropout and a lack of new admissions among people who use non-opioid substances. This article argues that including non-opioid substances in MMT's mandate restricts its ability to improve public health, including by preventing overdoses, and recommends instead that MMT adopt a more individualized approach, shaped by the needs and goals of the patient rather than those of the clinician.

Cancer Biomarkers for Integrative Oncology.

PURPOSE OF REVIEW: There has been an increasing interest in using complementary and alternative medicine (CAM) approaches to treat cancer. It is therefore relevant and timely to determine if CAM biomarkers can be identified and developed to guide cancer diagnosis and treatment. Herein, we review the status of cancer biomarkers in CAM research and treatment to stimulate further research in this area. RECENT FINDINGS: Studies on promising anti-cancer natural products, such as PHY906, honokiol, bryostatin-1, and sulforaphane have demonstrated the existence of potential cancer biomarker(s). Additional studies are required to further develop and ultimately validate these biomarkers that can predict clinical activity of the anti-cancer natural products used alone or in combination with chemotherapeutic agents. A systematic approach is needed to identify and develop CAM treatment associated biomarkers and to define their role in facilitating clinical decision-making. The expectation is to use these biomarkers in determining potential options for CAM treatment, examining treatment effects and toxicity and/or clinical efficacy in patients with cancer.

State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research-NCI Strategic Workshop Highlights of Discussion Report.

In May 2016, the Office of Cancer Complementary and Alternative Medicine, Division of Cancer Diagnosis and Treatment, of the National Cancer Institute convened a special workshop focused on the State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research. The current state of the science, gaps, and future opportunities were reviewed and discussed by a distinguished panel of experts in this field of research, and the highlights of this meeting are reported herein.

Validating older adults' reports of less mind-wandering: An examination of eye movements and dispositional influences.

The Control Failures × Concerns theory perspective proposes that mind-wandering occurs, in part, because of failures to inhibit distracting thoughts from entering consciousness (McVay & Kane, 2012). Despite older adults (OAs) exhibiting poorer inhibition, they report less mind-wandering than do young adults (YAs). Proposed explanations include (a) that OAs' thought reports are less valid due to an unawareness of, or reluctance to report, task-unrelated thoughts (TUTs) and (b) that dispositional factors protect OAs from mind-wandering. The primary goal of the current study was to test the validity of thought reports via eye-tracking. A secondary goal was to examine whether OAs' greater mindfulness (Splevins, Smith, & Simpson, 2009) or more positive mood (Carstensen, Isaacowitz, & Charles, 1999) protects them from TUTs. We found that eye movement patterns predicted OAs' TUT reports and YAs' task-related interference (TRI, or thoughts about one's performance) reports. Additionally, poor comprehension was associated with more TUTs in both age groups and more TRI in YAs. These results support the validity of OAs' thought reports. Concerning the second aim of the study, OAs' greater tendency to observe their surroundings (a facet of mindfulness) was related to increased TRI, and OAs' more positive mood and greater motivation partially mediated age differences in TUTs. OAs' reduced TUT reports appear to be genuine and potentially related to dispositional factors.

Human thalamic and amygdala modulation in emotional scene perception.

Emotional scene perception is associated with enhanced activity in ventral occipitotemporal cortex and amygdala. While a growing body of research supports the perspective that emotional perception is organized via amygdala feedback to rostral ventral visual cortex, the contributions of high-order thalamic structures strongly associated with visual attention, specifically the mediodorsal nucleus and pulvinar, have not been well investigated. Here we sample the activity of amygdala, MDN, pulvinar, and extrastriate ventral visual regions with fMRI as a group of participants view a mixed series of pleasant, neutral, and unpleasant natural scenes, balanced for basic perceptual characteristics. The results demonstrate that all regions showed enhanced activity during emotionally arousing relative to neutral scene perception. Consistent with recent research, the latency of emotional discrimination across subcortical and visual cortical regions suggests a role for the amygdala in the early evaluation of scene emotion. These data support the perspective that higher order visual thalamic structures are sensitive to the emotional value of complex scene stimuli, and may serve in concert with amygdala and fusiform gyrus to modulate visual attention toward motivationally relevant cues.

Toward high-performance digital logic technology with carbon nanotubes.

The slow-down in traditional silicon complementary metal-oxide-semiconductor (CMOS) scaling (Moore's law) has created an opportunity for a disruptive innovation to bring the semiconductor industry into a postsilicon era. Due to their ultrathin body and ballistic transport, carbon nanotubes (CNTs) have the intrinsic transport and scaling properties to usher in this new era. The remaining challenges are largely materials-related and include obtaining purity levels suitable for logic technology, placement of CNTs at very tight (∼5 nm) pitch to allow for density scaling and source/drain contact scaling. This review examines the potential performance advantages of a CNT-based computing technology, outlines the remaining challenges, and describes the recent progress on these fronts. Although overcoming these issues will be challenging and will require a large, sustained effort from both industry and academia, the recent progress in the field is a cause for optimism that these materials can have an impact on future technologies.

The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors.

The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.

2500 years of European climate variability and human susceptibility.

Climate variations influenced the agricultural productivity, health risk, and conflict level of preindustrial societies. Discrimination between environmental and anthropogenic impacts on past civilizations, however, remains difficult because of the paucity of high-resolution paleoclimatic evidence. We present tree ring-based reconstructions of central European summer precipitation and temperature variability over the past 2500 years. Recent warming is unprecedented, but modern hydroclimatic variations may have at times been exceeded in magnitude and duration. Wet and warm summers occurred during periods of Roman and medieval prosperity. Increased climate variability from ~250 to 600 C.E. coincided with the demise of the western Roman Empire and the turmoil of the Migration Period. Such historical data may provide a basis for counteracting the recent political and fiscal reluctance to mitigate projected climate change.

The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells.

B-cell chronic lymphocytic leukemia (B-CLL) remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Honokiol is a natural product known to possess potent antineoplastic and antiangiogenic properties. We examined whether honokiol can overcome apoptotic resistance in primary tumor cells derived from B-CLL patients. Honokiol induced caspase-dependent cell death in all of the B-CLL cells examined and was more toxic toward B-CLL cells than to normal mononuclear cells, suggesting greater susceptibility of the malignant cells. Honokiol-induced apoptosis was characterized by the activation of caspase-3, -8, and -9 and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP). Exposure of B-CLL cells to honokiol resulted in up-regulation of Bcl2-associated protein (Bax) and down-regulation of the expression of the key survival protein myeloid-cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. In addition, B-CLL cells pretreated with interleukin-4 (IL-4), a cytokine known to support B-CLL survival, underwent apoptosis when subsequently incubated with honokiol, indicating that honokiol could also overcome the prosurvival effects of IL-4. Furthermore, honokiol enhanced cytotoxicity induced by fludarabine, cladribine, or chlorambucil. These data indicate that honokiol is a potent inducer of apoptosis in B-CLL cells and should be examined for further clinical application either as a single agent or in combination with other anticancer agents.

Sustained complete remission of CLL associated with the use of a Chinese herbal extract: case report and mechanistic analysis.

We report the case of a man with chronic lymphocytic leukemia (CLL) who, in the absence of cytotoxic chemotherapy, began taking a Chinese herbal extract. Shortly thereafter, he experienced a steady decline of his lymphocytosis and adenopathy, and he remains in remission now over 10 years later. The herbal extract inhibited the survival of primary CLL cells under in vitro culture conditions. However, it did not inhibit the activation of Akt or MAP kinase, nor did it inhibit the serine phosphorylation of STAT1. Thus, through an as yet unknown mechanism, this extract appears to exert pro-apoptotic effects in CLL.

Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo.

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent.