RASopathy mutations provide functional insight into the BRAF cysteine-rich domain and reveal the importance of autoinhibition in BRAF regulation.

BRAF is frequently mutated in human cancer and the RASopathy syndromes, with RASopathy mutations often observed in the cysteine-rich domain (CRD). Although the CRD participates in phosphatidylserine (PS) binding, the RAS-RAF interaction, and RAF autoinhibition, the impact of these activities on RAF function in normal and disease states is not well characterized. Here, we analyze a panel of CRD mutations and show that they increase BRAF activity by relieving autoinhibition and/or enhancing PS binding, with relief of autoinhibition being the major factor determining mutation severity. Further, we show that CRD-mediated autoinhibition prevents the constitutive plasma membrane localization of BRAF that causes increased RAS-dependent and RAS-independent function. Comparison of the BRAF- and CRAF-CRDs also indicates that the BRAF-CRD is a stronger mediator of autoinhibition and PS binding, and given the increased catalytic activity of BRAF, our studies reveal a more critical role for CRD-mediated autoinhibition in BRAF regulation.

The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

Challenges in Palliative Care in Latin America: A Narrative Review.

In "graying" populations with extended lifespans and survivable forms of cancer, palliative services become increasingly important but may be difficult to introduce into public discourse, public policy, and healthcare systems. Latin America (LATAM) faces many challenges as it introduces and, in some cases, develops its palliative care programs; though the challenges faced here are in many ways universal ones, LATAM approaches may be unique and based on the region's specific culture, politics, and economics. This narrative review based on a literature search identified 10 main themes that can be interpreted as challenges and opportunities for palliative care in LATAM. These challenges are integrating palliation into healthcare systems; public policy and funding; therapeutic obstinacy; changing demographics; access to services; analgesia; the role of religion, spirituality, and folk medicine; social determinants of palliative care; low health literacy; and limited clinician training. Some of the LATAM nations have palliative programs and palliative care training in place while others are developing these systems. Integrating this care into existing healthcare and reimbursement systems has been a challenge. A notable challenge in LATAM is also access to care since palliative programs tend to cluster in metropolitan areas and create hardships for rural citizens to access them. The better-defined role of familial caregivers and telehealth may be important factors in the expansion of palliative care in LATAM and beyond.

An update on pharmacotherapy for trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options. AREAS COVERED: The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia. EXPERT OPINION: In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.

Trigeminal neuralgia is a relatively rare condition that usually affects one side of the face below the eye around the cheekbone. The cause of trigeminal neuralgia is sometimes a damaged nerve or a nerve that has lost part of its outer protective sheath (myelin). However, trigeminal neuralgia may have other neurological causes as well. Pain can be triggered by touch, pressure, or chewing and it tends to occur in very painful brief attacks followed by pauses with little or no pain. There are two types of drug treatment for trigeminal neuralgia: drugs to stop an ongoing attack (which are often administered in an emergency room or hospital intravenously) and drugs that are taken orally over the long term to reduce or prevent attacks.The two most effective drugs for trigeminal neuralgia are carbamazepine and oxcarbazepine, which are actually drugs to prevent seizures. They are effective in reducing the pain intensity and number of attacks of trigeminal neuralgia but they have side effects. In fact, these side effects can be so severe that people stop taking the drugs.Many new drugs have come to market recently that may work for trigeminal neuralgia, although none was specifically developed for this use. The newest generation of anti-seizure medications including eslicarbazepine, lacosamide, levetiracetam, and retigabine, may be just as effective as the older carbamazepine and oxcarbazepine drugs with fewer side effects. Clinical studies are needed to test them in trigeminal neuralgia patients but their mechanisms of action suggest that they might work well.There are some new drugs developed for migraine headache that inhibit a substance in the body called CGRP. Migraine headaches and trigeminal neuralgia have some of the same symptoms but they are different conditions but both involve too much CGRP.Other new drugs include lasmiditan, pimozide (used for Tourette syndrome), tizanidine (muscle relaxant), lamotrigine and vixotrigine (anti-seizure drugs) may also be beneficial. It may be that people with trigeminal neuralgia will have to take combination therapy, the use of two or more drugs with different mechanisms of action. Older drugs like ketamine and cannabinoids are also being considered as possible add-on agents for therapy for trigeminal neuralgia.

Red Wine as an Aromatase Inhibitor: A Narrative Review.

As estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than serum estrogen, aromatase inhibitors for treating breast carcinomas in postmenopausal women have been developed. As the aromatase enzyme converts endogenous androgen to estrogenic compounds, its blockade lowers the in situ production of estrogen, demonstrated to encourage tumor proliferation. Red wine, but not white wine, may have aromatase-inhibiting properties that are being elucidated, although the exact mechanisms of action are not known. Polyphenols, tannins, and resveratrol have all been implicated as aromatase blockers, and there may also be synergistic interplay among selected constituents. The role of red wine would be in chemoprevention, the use of natural or synthetic substances to retard, block, or reverse cancer. One gene encodes aromatase, so aromatase inhibition would stop endogenous estrogen production. The role of aromatase inhibition in breast cancer in premenopausal women is not clear. While animal studies have demonstrated that red wine contains constituents that could block aromatase in vivo, the benefits also exist with nonalcoholic grape seed extract. Further investigation is needed but there are challenges in designing appropriate clinical trials for a substance as variable as red wine. While there is insufficient evidence to advocate for red wine as an aromatase inhibitor, there is sufficient evidence to warrant further investigation.

The Emergence of the Old Drug Captagon as a New Illicit Drug: A Narrative Review.

First developed in the 1960s in Europe and approved briefly for use in the United States, fenethylline (sold as Captagon, one of its early trade names) is now a prominent drug of abuse in the Eastern Mediterranean Region. The drug was withdrawn from the United States market because of side effects that included hallucinations, visual distortions, and psychosis; it has also been linked to rare cases of myocardial infarction, seizures, and delusions. The chemical synthesis of fenethylline is straightforward and inexpensive. Manufactured in clandestine labs in Southern Europe and the Middle East, these amphetamines had been used by affluent Middle Eastern young people for recreation or study aids. Captagon has periodically emerged as a drug used in combat and conflict, and it was implicated in the 2015 riots in Paris. It has been described as "chemical courage" for combatants giving them focus, energy, and endurance in battle situations. Captagon is addictive but no cases of direct captagon-associated mortality have been reported. The use of drugs in war is nothing new, but captagon is also used heavily in the civilian population in war-torn areas to help them cope with food insecurity and maintain courage in dangerous situations. Captagon production and distribution drives the Syrian economy, but the drug's use is limited to certain regions and is rarely seen in North America. The drug is available online, but product may be contaminated with the inclusion of procaine, caffeine, or other substances.

The Challenges in Clinical Diagnosis of Trigeminal Neuralgia: A Review.

The lack of established laboratory tests or biomarkers for trigeminal neuralgia (TN) makes diagnosing this relatively rare condition extremely challenging. Trigeminal nerve compression observable on magnetic resonance imaging may indicate TN, but many patients do not have visible lesions or compression. In particular, TN may be confused with migraine, cluster headache, temporomandibular disorder, and other types of headache. An accurate diagnosis is imperative for proper treatment since these conditions do not respond to the same treatment. Many symptoms of these headaches can be vague or overlap, and clinicians depend in large measure on the subjective reports of their patients. Nevertheless, it is imperative to diagnose TN better, which can cause excruciating pain, reduce the quality of life, and even result in disability. It is possible that TN is underestimated.

From Antidepressant Tianeptine to Street Drug ZaZa: A Narrative Review.

Tianeptine is often incorrectly described as a selective serotonin reuptake inhibitor, but it actually is a µ-opioid receptor agonist with anxiolytic effects. It has been approved since the last 1980s in about 24 countries as a treatment for depression, but it was never cleared to market in the United States for this purpose. Nevertheless, tianeptine joined the billion-dollar US market of nootropics as ZaZa or Tianna Red and is widely available online and in small shops without a prescription, to the point that it has been nicknamed "gas station heroin." While the therapeutic dose range is about 25 to 50 mg/day, tianeptine abusers may take 100 times that amount. Tolerance occurs rapidly and users who seek to recapture the short-lived euphoric effects of the drug have to take more and more. Social media has peer-support sites for those trying to discontinue tianeptine. Tianeptine is associated with multiple side effects at high doses along with dependence, withdrawal symptoms, toxicity, respiratory depression, and even mortality. Agitation is more often a presenting symptom of withdrawal than toxicity. Tianeptine is often used by polysubstance drug abusers who may be unaware of the drug's dangers. Few clinicians are aware of tianeptine and most urine assays do not screen for it. Greater awareness is needed for this drug and steps must be taken as tianeptine or "gas station heroin" is emerging as a new public health threat.

RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.

RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.