Primary Headache Associated with Sexual Activity: A Review of the Literature.

PURPOSE OF REVIEW: This review summarizes the evolution in diagnosis, evaluation, and treatment of primary headache associated with sexual activity (PHASA). RECENT FINDINGS: Despite increased access to patient information and advances in imaging, the pathophysiology of PHASA remains not fully understood. There are many secondary headaches that may present with headache during sexual activity, and a thorough workup is indicated to rule out potentially life-threatening etiologies. Many recent case series discuss the efficacy of known treatments of PHASA, as well as suggest other potential therapies for this condition including the newer CGRP-targeted therapies. Headaches during sexual activity can be worrisome events which necessitate urgent evaluation, particularly when presenting with sudden-onset and severe "thunderclap" headaches. A thorough workup including imaging should be conducted to rule out etiologies such as subarachnoid hemorrhage, reversible cerebral vasoconstrictive syndrome (RCVS), vasospasm, and dissection. PHASA is commonly comorbid with migraine, tension-type headache, exertional headache, and hypertension. PHASA can present as a dull headache that progresses with sexual excitement, or an explosive headache at or around orgasm. Pain is primarily occipital, diffuse, and bilateral. The headaches are discrete, recurrent events with bouts that typically self-resolve, but may also relapse and remit or continue chronically in some patients. PHASA can be treated preemptively with indomethacin and triptans administered prior to sexual activity, or treated prophylactically with beta-blockers, topiramate, and calcium channel blockers. CGRP-targeted therapies may provide relief in PHASA based on a few case reports, but there are no randomized controlled trials looking at specific efficacy for these therapies.

Different effects of NK cells and NK-derived soluble factors on cell lines derived from primary or metastatic pancreatic cancers.

Natural killer (NK) cells are cytotoxic lymphoid cells that play a key role in defenses against tumors. However, their function may be severely impaired in patients with pancreatic adenocarcinoma (PA). Indeed, PA cells release soluble factors, thereby generating an immunosuppressive environment that dysregulates NK-cell cytolytic function and favors tumor immune evasion. Here, we analyzed the interactions between NK and PA cells using the PANC-1 and CAPAN-1 cell lines derived from a ductal PA and metastatic lesion, respectively. Metastatic and nonmetastatic cell lines were both able to impair NK cytolytic activity. An analysis of the effect of NK cells and NK-cell-derived exosomes revealed substantial differences between the two cell lines. Thus, NK cells displayed higher cytotoxicity against nonmetastatic PA cells than metastatic PA cells in both 2D cultures and in a 3D extracellular matrix cell system. In addition, NK-derived exosomes could penetrate only PANC-1 spheroids and induce cell killing. Remarkably, when PANC-1 cells were exposed to NK-derived soluble factors, they displayed substantial changes in the expression of genes involved in epithelial-to-mesenchymal transition (EMT) and acquired resistance to NK-mediated cytolysis. These results, together with their correlation with poor clinical outcomes in PA patients, suggest that the induction of resistance to cytolysis upon exposure to NK-derived soluble factors could reflect the occurrence of EMT in tumor cells. Our data indicate that a deeper investigation of the interaction between NK cells and tumor cells may be crucial for immunotherapy, possibly improving the outcome of PA treatment by targeting critical steps of NK-tumor cell crosstalk.

The Exploration of Cannabis and Cannabinoid Therapies for Migraine.

PURPOSE OF REVIEW: There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use. RECENT FINDINGS: Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.

Triptan medication use among patients with migraine with contraindications in the US.

OBJECTIVE: We sought to investigate the prevalence of triptan use among patients with migraine who have contraindications to triptan usage, and to explore specifics of the medication prescribed, dosage, and route of administration. BACKGROUND: Triptan medications are a mainstay of acute migraine therapy, but little is known about prevalence and patterns of triptan prescribing among patients with contraindications in the United States. METHODS: In this retrospective cohort study, we used data from the IBM Marketscan database to identify patients aged ≥ 18 years with migraine from January 1, 2016, to December 31, 2017, using International Classification of Diseases, Clinical Modification 10 codes. Contraindications to triptan medications were identified by review of package labels as listed on the US Food and Drug Administration website. Triptan medications were identified from the IBM Micromedex Redbook linked to prescription claims along with route of administration and dosage. RESULTS: Of 1,038,472 individuals diagnosed with migraine, 400,112 (38.5%) were prescribed triptan medication, and of those who were prescribed a triptan, 55,707 (13.9%) had at least one contraindication, with the most common contraindication being cardiac arrhythmia (33,696/400,112 individuals, 8.4%) followed by cerebrovascular disease (14,787/400,112, 3.7%) and coronary artery disease (10,236/400,112, 2.6%). Sumatriptan was the most prescribed triptan (261,736/1,038,472, 25.2%), and the subcutaneous and intranasal routes were more commonly prescribed among those with contraindications compared with those without contraindications. DISCUSSION: A substantial proportion of patients with migraine with contraindications were prescribed triptan medications. These findings call for further research on the outcomes of patients with medical contraindications who are prescribed triptan medications, and for greater clarity in prescribing guidelines about the optimal approach for acute therapy among patients with migraine.

Glucocorticoids and the cytokines IL-12, IL-15, and IL-18 present in the tumor microenvironment induce PD-1 expression on human natural killer cells.

BACKGROUND: Programmed cell death protein 1 (PD-1)-immune checkpoint blockade has provided significant clinical efficacy across various types of cancer by unleashing both T and natural killer (NK) cell-mediated antitumor responses. However, resistance to immunotherapy occurs for many patients, rendering the identification of the mechanisms that control PD-1 expression extremely important to increase the response to the therapy. OBJECTIVE: We sought to identify the stimuli and the molecular mechanisms that induce the de novo PD-1 expression on human NK cells in the tumor setting. METHODS: NK cells freshly isolated from peripheral blood of healthy donors were stimulated with different combinations of molecules, and PD-1 expression was studied at the mRNA and protein levels. Moreover, ex vivo analysis of tumor microenvironment and NK cell phenotype was performed. RESULTS: Glucocorticoids are indispensable for PD-1 induction on human NK cells, in cooperation with a combination of cytokines that are abundant at the tumor site. Mechanistically, glucocorticoids together with IL-12, IL-15, and IL-18 not only upregulate PDCD1 transcription, but also activate a previously unrecognized transcriptional program leading to enhanced mRNA translation and resulting in an increased PD-1 amount in NK cells. CONCLUSIONS: These results provide evidence of a novel immune suppressive mechanism of glucocorticoids involving the transcriptional and translational control of an important immune checkpoint.

MiR-22, a serum predictor of poor outcome and therapy response in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous neoplasm where prognostication and therapeutic decision are challenging. The available prognostic tools are not able to identify all patients refractory to treatment. MicroRNAs, small RNAs frequently deregulated in cancer, stably circulate in biofluids, representing interesting candidates for non-invasive biomarkers. Here we validated serum miR-22, an evolutionarily conserved microRNA, as a prognostic/predictive biomarker in DLBCL. Moreover, we found that its expression and release from DLBCL cells are related to therapy response and adversely affect cell proliferation. These results suggest that miR-22 is a promising complementary or even independent non-invasive biomarker for DLBCL management.

Headache in transgender and gender-diverse patients: A narrative review.

OBJECTIVE: To summarize the unique aspects of managing headache in gender minorities and current research in this area including the potential relationship between gender-affirming hormone therapy (GAHT) and headache. BACKGROUND: The study of headache in gender minorities is intrinsically important. Gender minorities are medically underserved, and their medical care to date has been limited by socioeconomic disadvantages including stigma and an unsupportive clinical environment. Despite the rising population of transgender and gender-diverse adults and youth, headache research has also been limited. Knowledge of hormonal effects on headache in cisgender patients raises the question of possible effects of GAHT on transgender patients. METHODS/RESULTS: The manuscript is a narrative review of current best practices in treating transgender patients, including the use of appropriate terminology and ways to create a supportive environment. It also contains current guidelines on GAHT and reviews drug-drug interactions and secondary headache related to hormone therapy. We also review transgender headache research and related research on hormonal effects on headache in cisgender individuals. CONCLUSION: Creating a supportive environment for transgender and gender-diverse patients and being knowledgeable about GAHT are key to providing quality headache care. This review identifies further research needs for this population including the epidemiology of headache disorders in sexual minorities and the potential effects of GAHT on headache disorders in transgender patients.

The current state of headache medicine education in the United States and Canada: An observational, survey-based study of neurology clerkship directors and curriculum deans.

OBJECTIVE: To investigate the current headache medicine education paradigm in allopathic and osteopathic medical schools in the United States and Canada. BACKGROUND: There is a disparity in the number of clinicians specially trained to treat patients with headache disorders and the number of people who have them. Early education and exposure to headache medicine is crucial to address this disparity. However, the current state of headache education within medical schools across the United States and Canada is unknown. METHODS: The authors created a medical student headache education survey, which is a 20-question REDCap survey that was distributed via email to the neurology clerkship director, curriculum dean, or similar role at each US and Canadian MD or DO conferring medical school. The email listserv was created using the American Academy of Neurology Clerkship Directory, the Association of American Medical Colleges Organization Directory, the American Association of College of Osteopathic Medicine Organization Directory, manual searches of the institutions' websites, and phone calls and emails to administrators as needed. RESULTS: Of the 249 individuals contacted, 78 completed the survey, yielding a response rate of 31.3%. Of those responses, 84.6% of respondents (66/78) reported that their institution has at least one mandatory session on headache disorders. Many of these sessions (72.7% (48/78)) occurred during preclinical training, and 74.2% (49/78) occurred as part of the clinical curricula. Of respondents, 44.9% (39/78) reported that their institutions coordinate headache education across training levels (i.e., from preclinical to clinical), and only 17.9% (14/78) coordinate across clinical rotations. The most common topics covered were headache red flags, migraine, pharmacologic management, and differentiating primary versus secondary headache. 65.4% of respondents (51/78) felt that the preclinical headache curriculum prepares their students for the clinical experience, and 55.1% (43/78) felt that medical students were learning enough about headache medicine at their institution. Barriers to educating medical students about headache included insufficient time during courses, lack of administrative support in curricula development, lack of available resources, and lack of student interest. Case-based learning modules and online lectures were the most desired educational materials to improve medical student headache education at their institution. CONCLUSIONS: The majority of medical schools report incorporating headache medicine education into preclinical or clinical curricula and cover a range of topics in headache medicine. Yet there remains a lack of consistency, with some reporting limited headache education, citing barriers such as lack of administrative support and available educational resources. There is also variation in what is being taught at the medical student level. Future projects should aim to address said barriers, with the goal of providing a standardized headache medicine curriculum for use across medical schools.

A retrospective cohort study of clinical factors, visit patterns, and demographic factors associated with use of remote communications in patients with headache.

OBJECTIVE: To identify the characteristics associated with high utilization of remote communications (RCs) in patients with headache. BACKGROUND: Patients with headache frequently communicate with their providers using secure portal messaging and telephone calls. However, clinical and demographic factors as well as visit patterns associated with RC utilization remain poorly characterized. METHODS: We retrospectively analyzed data from patients with headache who were evaluated in the ambulatory neurology faculty practice at the Icahn School of Medicine at Mount Sinai in New York between January 1 and June 30, 2019. We extracted clinical and demographic characteristics, total office visits, secure MyChart portal messages, and telephone encounters from our institutional data warehouse. We defined high RC and MyChart utilization as the top tertile of RC and MyChart message volume, respectively, and assessed the relationship between patient characteristics and high RC (primary outcome), as well as high MyChart utilization (secondary outcome). We characterized the relationship between clinicodemographic characteristics and the ratio of MyChart messages to total RCs (secondary outcome). RESULTS: We identified 1390 patients, of whom 477 (34.3%) were high RC utilizers and 321 (23.1%) were high MyChart utilizers. High RC utilizers generated 3306/3921 (84.3%) RCs. The presence of chronic headache (aOR 2.31, 95% CI 1.75-3.03, p < 0.0001), cluster headache (aOR 18.3, 95% CI 5.0-71.7, p = 0.001), and migraine (aOR 3.82, 95% CI 1.93-9.3, p = 0.011) was associated with high RC utilization. Patients ≥65 years of age were less likely to engage in MyChart messaging as a proportion of RC (191/680, 28.1%) compared with patients 18-30 years of age (243/620, 39.2%, p = 0.049) and 30-64 years of age (1172/2721, 43.1%, p < 0.0001). CONCLUSIONS: A minority of patients with headache (477/1390; 34.3%) generated the majority (3306/3921; 84.3%) of RCs. Our findings should be validated in external patient cohorts with the objective of developing strategies to optimize RC utilization.

Gender Minority Stress, Psychiatric Comorbidities, and the Experience of Migraine in Transgender and Gender-Diverse Individuals: a Narrative Review.

PURPOSE OF REVIEW: This review aims to discuss the experience of migraine in transgender and gender-diverse individuals as it relates to other psychiatric comorbidities such as anxiety, depression, PTSD, and others. As this population faces stigma and discrimination, literature posits that gender minority stress can also contribute to the experience of pain in these individuals. RECENT FINDINGS: Though there is little explicit data on these topics, more recent studies have explored the concept of gender minority stress and how stigma and discrimination can affect health outcomes and overall perception of health. These findings, as well as data on psychiatric comorbidities in cisgender individuals with migraine, can be extrapolated to understand how gender minority individuals may experience migraine. Research has demonstrated that stigma and discrimination can affect health outcomes in the transgender and gender-diverse community. A recent study has shown that sexual minority stress associated with stigma, discrimination, and barriers to care can exacerbate migraine. It is known that psychiatric comorbidities such as anxiety, depression, and PTSD can affect migraine frequency and severity in cisgender individuals. Though there are no specific studies in the transgender and gender-diverse patient population, these highly prevalent mental health conditions could potentially contribute to their migraine experience. Hormones, as well, may affect mood in those on gender-affirming hormone therapy, with some studies exploring how this may have both a direct and indirect relationship with migraine. There are clear knowledge gaps that can be addressed by future research in these areas to better understand the migraine experience in transgender and gender-diverse individuals and improve overall care.

Headaches in hypermobility syndromes: A pain in the neck?

Headache and neck pain (cervicalgia) are frequently reported among patients with joint hypermobility but the prevalence and scope of these symptoms has not been studied in the era of contemporary Ehlers-Danlos and hypermobility disorder nosology. We performed a single-center retrospective study on the incidence of head and neck symptoms in 140 patients with hypermobility disorders over a 2-year period. Overall, 93 patients (66%) reported either headache or neck pain with 49 of those (53%) reporting both. Migraine (83%) was the most common headache type among those with headache disorders and cervical spondylosis (61%) the most common pathology among those with neck symptoms. Fifty-nine percent of spondylosis patients who underwent cervical facet procedures reported significant improvement in neck and head symptoms. Of patients with both head and neck complaints, 82% had both migraine and spondylosis, which, when combined with the high response rate to injections raises the possibility of cervicogenic headache. In this large multidisciplinary retrospective study of patients with hypermobility disorders, head and neck symptoms were highly prevalent, with migraine and cervical spondylosis common, often coexisting, and frequently responsive to targeted therapy for the cervical spine suggesting that degenerative spinal pathology may cause or contribute to headache symptoms in some patients with hypermobility disorders.

Exercise and Migraine Prevention: a Review of the Literature.

PURPOSE OF REVIEW: This review intends to characterize the recent literature pertaining to the role of aerobic exercise in the prevention of migraine. Areas of consensus within that literature may be used to guide clinical practice, allowing for the promulgation of evidence-based practice recommendations. RECENT FINDINGS: The past decade has seen the publication of numerous high-quality studies that explore aspects of exercise's effects on migraine prevention, including its success as a stand-alone prevention strategy, as well as its non-inferiority to some pharmacologic preventive measures. Exercise often tops providers' lists of recommended lifestyle modifications that help reduce migraine burden. Biologically, exercise suppresses inflammatory modulators, including numerous cytokines, and stress hormones, like growth hormone and cortisol. Exercise has also been shown to affect microvascular health, which may be implicated in cortical spreading depression. Psychologically, there is evidence that exercise improves migraine self-efficacy and internalizes the locus of control, leading to reduced migraine burden. Randomized control trials have demonstrated that a sufficiently rigorous aerobic exercise regimen alone is sufficient to yield a statistically significant reduction in migraine frequency, intensity, and duration. Higher-intensity training appears to confer more benefit. Studies have also demonstrated non-inferiority of exercise compared with certain pharmacologic prophylactic interventions, like topiramate. However, the addition of exercise to a traditional preventive regimen may provide added benefit. Special populations, like those with comorbid neck pain or tension headache, may benefit from exercise; and patients who cannot tolerate high-impact exercise may even benefit from low-impact exercise like yoga. Therefore, exercise is a reasonable evidence-based recommendation for migraine prevention.

Episodic Migraine Comorbidities: Avoiding Pitfalls and Taking Therapeutic Opportunities.

Migraine is a common neurologic disorder. This article will discuss a few factors that influence migraine (mostly episodic) and its treatment, such as sleep, obstructive sleep apnea (OSA), obesity, and affective disorders, as well as autoimmune diseases. Practitioners must be aware of these coexisting conditions (comorbidities) as they affect treatment. It is noted in literature that both the quantity (too much or too few hours) and the quality (OSA related) of sleep may worsen migraine frequency. An associated risk factor for OSA, obesity also increases migraine frequency in episodic migraine cases. A bidirectional relationship with migraine along with depression and anxiety is debated in the literature. Retrospective cohort studies are undecided and lack statistical significance, but prospective studies do show promising results on treatment of anxiety and depression as a means of improving migraine control. Finally, we address the topic of autoimmune diseases and migraine. While few studies exist at this time, there are cohort study groups looking into the association between rheumatoid arthritis, hypothyroidism, and antiphospholipid antibody. There is also evidence for the link between migraine and vascular diseases, including coronary and cerebral diseases. We suggest that these comorbid conditions be taken into account and individualized for each patient along with their pharmaceutical regimen. Physicians should seek a multifactorial treatment plan including diet, exercise, and healthy living to reduce migraine frequency.

Neurologic Care for Transgender and Gender-Diverse People: A Review of Current Evidence and Clinical Implications.

Purpose of Review: To summarize the literature on neurologic care for transgender and gender-diverse (TGD) people and provide implications for clinical practice. Recent Findings: There are limited data on the frequency and management of neurologic conditions among TGD people. TGD people have a higher prevalence of various neurologic conditions compared with cisgender or general population cohorts, including migraine, subjective cognitive decline, sleep disturbances, functional disorders, and cerebrovascular disease. Gender-affirming hormone therapy interacts with commonly prescribed neurologic medications and increases stroke risk among transfeminine people. Sex hormones and sex chromosomes may play a role in neurodegeneration and disability progression in neuroimmunologic diseases. Clitoral reduction surgeries on intersex children can cause neurologic disability and sexual dysfunction in adulthood. Socioeconomic disparities among TGD people contribute to health care barriers. Summary: Neurologists should consider the unique experiences and health care needs of TGD people in their clinical practice and research protocols.

An Experimental Setup to Test Obstacle-Dealing Capabilities of Prosthetic Feet.

Small obstacles on the ground often lead to a fall when caught with commercial prosthetic feet. Despite some recently developed feet can actively control the ankle angle, for instance over slopes, their flat and rigid sole remains a cause of instability on uneven grounds. Soft robotic feet were recently proposed to tackle that issue; however, they lack consistent experimental validation. Therefore, this paper describes the experimental setup realized to test soft and rigid prosthetic feet with lower-limb prosthetic users. It includes a wooden walkway and differently shaped obstacles. It was preliminary validated with an able-bodied subject, the same subject walking on commercial prostheses through modified walking boots, and with a prosthetic user. They performed walking firstly on even ground, and secondly on even ground stepping on one of the obstacles. Results in terms of vertical ground reaction force and knee moments in both the sagittal and frontal planes show how the poor performance of commonly used prostheses is exacerbated in case of obstacles. The prosthetic user, indeed, noticeably relies on the sound leg to compensate for the stiff and unstable interaction of the prosthetic limb with the obstacle. Therefore, since the limitations of non-adaptive prosthetic feet in obstacle-dealing emerge from the experiments, as expected, this study justifies the use of the setup for investigating the performance of soft feet on uneven grounds and obstacle negotiation.

MicroRNA analysis of Natural Killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against pancreatic cancer cells.

Natural Killer (NK) cells are important components of the immune system in the defense against tumor growth and metastasis. They release exosomes containing proteins and nucleic acids, including microRNAs (miRNAs). NK-derived exosomes play a role in the anti-tumor NK cell function since they are able to recognize and kill cancer cells. However, the involvement of exosomal miRNAs in the function of NK exosomes is poorly understood. In this study, we explored the miRNA content of NK exosomes by microarray as compared to their cellular counterparts. The expression of selected miRNAs and lytic potential of NK exosomes against childhood B acute lymphoblastic leukemia cells after co-cultures with pancreatic cancer cells were also evaluated. We identified a small subset of miRNAs, including miR-16-5p, miR-342-3p, miR-24-3p, miR-92a-3p and let-7b-5p that is highly expressed in NK exosomes. Moreover, we provide evidence that NK exosomes efficiently increase let-7b-5p expression in pancreatic cancer cells and induce inhibition of cell proliferation by targeting the cell cycle regulator CDK6. Let-7b-5p transfer by NK exosomes could represent a novel mechanism by which NK cells counteract tumor growth. However, both cytolytic activity and miRNA content of NK exosomes were reduced upon co-culture with pancreatic cancer cells. Alteration in the miRNA cargo of NK exosomes, together with their reduced cytotoxic activity, could represent another strategy exerted by cancer to evade the immune response. Our study provides new information on the molecular mechanisms used by NK exosomes to exert anti-tumor-activity and offers new clues to integrate cancer treatments with NK exosomes.

Healthcare utilization impacts of an eConsult program for headache at an academic medical center.

INTRODUCTION: Interprofessional consultations ("eConsults") can reduce healthcare utilization. However, the impact of eConsults on healthcare utilization remains poorly characterized among patients with headache. METHODS: We performed a retrospective, 1:1 matched cohort study comparing patients evaluated for headache via eConsult request or in-person referral at the Mount Sinai Health System in New York. Groups were matched on clinical and demographic characteristics. Our primary outcome was one or more outpatient headache-related encounters in 6 months following referral date. Secondary outcomes included one or more all-cause outpatient neurology and headache-related emergency department (ED) encounters during the same period. We used univariable and multivariable logistic regression to model associations between independent variables and outcomes. RESULTS: We identified 74 patients with headache eConsults who were matched to 74 patients with in-person referrals. Patients in the eConsult group were less likely to achieve the primary outcome (29.7% vs 62.2%, P < 0.0001) or have an all-cause outpatient neurology encounter (33.8% vs 79.7%, P < 0.0001) than patients in the comparison group. Both groups did not significantly differ by headache-related ED encounters. In multivariable analyses, patients in the eConsult group had significantly lower odds of having one or more headache-related or all-cause neurology encounters than patients in the comparison group (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1-0.6; OR 0.1, 95% CI 0.1-0.3, respectively). DISCUSSION: In comparison to in-person referrals, eConsult requests for headache were associated with reduced likelihood of outpatient neurology encounters in the short-term but not with differential use of headache-related ED encounters. Larger-scale, prospective studies should validate our findings and assess patient outcomes.

Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells.

Although considered promising for use in drug-eluting stents (DES), tacrolimus failed clinically. Tacrolimus inhibits growth factor production but can also act as a growth factor on vascular smooth muscle cells (VSMC). This unexpected proliferative stimulus could reverse the beneficial effects of the drug on restenosis. We hypothesized that tacrolimus' association with statins, which lower cholesterol and impair cell proliferation, could restore tacrolimus' beneficial effect by abrogating the aberrant proliferative stimulus. Additionally, since maintenance of endothelial function represents a challenge for new-generation DES, we investigated the combined effect of tacrolimus and atorvastatin on endothelial cells. Human VSMC and umbilical vein endothelial cells (HUVEC) were incubated with 100 nM tacrolimus and increasing doses of atorvastatin (0-3.0 µM). Atorvastatin plus tacrolimus dose-dependently inhibited VSMC proliferation. The percentage of cells incorporating 5-bromo-2'-deoxyuridine (BrdU) in their DNA was 49 ± 14% under basal conditions, 62 ± 15% (P = 0.01) with tacrolimus, 40 ± 22% with 3 µM atorvastatin, and 30 ± 7% (P < 0.05) with 3 µM atorvastatin plus tacrolimus. Atorvastatin downregulated ß-catenin, Erk1 and Erk2, and cyclin B in tacrolimus-stimulated VSMC. In contrast, atorvastatin plus tacrolimus did not affect proliferation of endothelial cells. The percentage of HUVEC incorporating BrdU in their DNA was 47 ± 8% under basal conditions, 58 ± 6% (P = 0.01) with tacrolimus, 45 ± 4% with 3 µM atorvastatin, and 49 ± 1% with 3 µM atorvastatin plus tacrolimus. Both agents stimulated endoglin production by HUVEC. Taken together, these results suggest that, when combined with tacrolimus, atorvastatin exerts a dose-dependent antiproliferative effect on VSMC. In contrast, atorvastatin acts in concert with tacrolimus in HUVEC to stimulate production of endoglin, a factor that has an important role in endothelial repair. Our study supports the conclusion that prevention of postcoronary in-stent restenosis and late thrombosis may benefit of concomitant association of tacrolimus and high doses of atorvastatin.

Interaction Between MDSC and NK Cells in Solid and Hematological Malignancies: Impact on HSCT.

Myeloid derived suppressor cells (MDSC) are heterogeneous populations that through the release of soluble factors and/or by cell-to-cell interactions suppress both innate and adaptive immune effector cells. In pathological conditions, characterized by the presence of inflammation, a partial block in the differentiation potential of myeloid precursors causes an accumulation of these immunosuppressive cell subsets both in peripheral blood and in tissues. On the contrary, NK cells represent a major player of innate immunity able to counteract tumor growth. The anti-tumor activity of NK cells is primarily related to their cytolytic potential and to the secretion of soluble factors or cytokines that may act on tumors either directly or indirectly upon the recruitment of other cell types. NK cells have been shown to play a fundamental role in haploidentical hemopoietic stem cell transplantation (HSCT), for the therapy of high-risk leukemias. A deeper analysis of MDSC functional effects demonstrated that these cells are capable, through several mechanisms, to reduce the potent GvL activity exerted by NK cells. It is conceivable that, in this transplantation setting, the MDSC-removal or -inactivation may represent a promising strategy to restore the anti-leukemia effect mediated by NK cells. Thus, a better knowledge of the cellular interactions occurring in the tumor microenvironment could promote the development of novel therapeutic strategies for the treatment of solid and hematological malignances.

Polymorphonuclear Myeloid-Derived Suppressor Cells Are Abundant in Peripheral Blood of Cancer Patients and Suppress Natural Killer Cell Anti-Tumor Activity.

Tumor microenvironment (TME) includes a wide variety of cell types and soluble factors capable of suppressing immune-responses. While the role of NK cells in TME has been analyzed, limited information is available on the presence and the effect of polymorphonuclear (PMN) myeloid-derived suppressor cells, (MDSC). Among the immunomodulatory cells present in TME, MDSC are potentially efficient in counteracting the anti-tumor activity of several effector cells. We show that PMN-MDSC are present in high numbers in the PB of patients with primary or metastatic lung tumor. Their frequency correlated with the overall survival of patients. In addition, it inversely correlated with low frequencies of NK cells both in the PB and in tumor lesions. Moreover, such NK cells displayed an impaired anti-tumor activity, even those isolated from PB. The compromised function of NK cells was consequent to their interaction with PMN-MDSC. Indeed, we show that the expression of major activating NK receptors, the NK cytolytic activity and the cytokine production were inhibited upon co-culture with PMN-MDSC through both cell-to-cell contact and soluble factors. In this context, we show that exosomes derived from PMN-MDSC are responsible of a significant immunosuppressive effect on NK cell-mediated anti-tumor activity. Our data may provide a novel useful tool to implement the tumor immunoscore. Indeed, the detection of PMN-MDSC in the PB may be of prognostic value, providing clues on the presence and extension of both adult and pediatric tumors and information on the efficacy not only of immune response but also of immunotherapy and, possibly, on the clinical outcome.