Late Onset of Cardiac Metastasis of a Melanoma following Nivolumab Immunotherapy.

In this report, we present a case of cardiac metastasis of a malignant melanoma originating from the nasal cavity and presenting with cardiac tamponade detected during immunotherapy. The patient was a 66-year-old man diagnosed with malignant melanoma of the right nasal cavity 4 years ago. Two years ago, the size of the melanoma increased making it unresectable; therefore, he was treated thrice with a combination therapy of nivolumab and ipilimumab. Subsequently, the treatment was changed to single-agent nivolumab therapy, which was continuously administered for one and a half years. Imaging evaluation conducted every 3 months showed no distant metastasis. General malaise occurred, and the patient visited our department. He was diagnosed to have cardiac tamponade using echocardiography and was admitted to the emergency department of our hospital. He underwent pericardiocentesis. Computed tomography revealed an irregular mass extending from the right atrium to the inferior vena cava, and malignant melanoma metastasis was diagnosed through catheter biopsy and histology. As the tumor was unresectable, radiotherapy (30 Gy/10 fractions) and dacarbazine administration were performed on the right atrial mass, and pericardial effusion improved.

Notch down-regulation in regenerated epidermis contributes to enhanced expression of interleukin-36α and suppression of keratinocyte differentiation during wound healing.

BACKGROUND: Notch signaling controls a number of cellular processes, including cell fate decisions, proliferation, differentiation, and survival/apoptosis, in multiple tissues. In the epidermis, Notch1 functions as a molecular switch that controls the transition of cells from an undifferentiated state into a differentiated state. OBJECTIVE: To clarify the functions of Notch in the regenerated epidermis during wound healing. METHODS: Wounds on mouse skin were immunostained. To investigate the functions of Notch, Notch was inhibited in primary keratinocytes by treatment with a γ-secretase inhibitor and by small interfering RNA-mediated knockdown, and was activated by a recombinant adenovirus approach. RESULTS: Notch1 and Notch2 were down-regulated in the regenerated epidermis during wound healing. To clarify the significance of this down-regulation, we examined its effect on expression of the interleukin (IL)-1 family of proinflammatory cytokines because wounds are exposed to pathogens from the outside world. Among the IL-1 family, IL-36α expression was induced by Notch inhibition. This was consistent with the decreased IL-36α expression in Notch-overexpressing keratinocytes. Notch down-regulation in the regenerated epidermis may reinforce defense against stress from the outside world by inducing IL-36α expression. Next, we examined the effects of Notch down-regulation on keratinocyte growth and differentiation. Notch down-regulation did not alter keratinocyte proliferation. On the other hand, Notch1 down-regulation suppressed induction of spinous layer-specific keratins (keratin1 and keratin10) in keratinocytes, which was consistent with the decreased expression of these keratins in the regenerated epidermis. The reduced levels of these keratins would increase cellular flexibility. CONCLUSION: Notch down-regulation in the epidermis appears to contribute to tissue regeneration during wound healing.

Toll-like receptor 4 signaling promotes the migration of human melanoma cells.

Immune cell Toll-like receptors (TLRs) recognize conserved microbial components, leading to immune and inflammatory responses. However, TLRs are also expressed in cancer cells, including melanoma cells, which express TLR2-4. TLR4 ligands have received attention as immunotherapies; therefore, we assessed the expression of TLR4 in human melanoma specimens (29 primary lesions and 28 metastatic lesions) representing different types of melanoma. A high percentage (≥ 90%) of melanoma lesions expressed TLR4, as judged by immunohistochemistry. Next, the role of TLR4 in cell proliferation and migration was assessed using the TLR4-positive (TLR4(+)) melanoma cell lines 501mel and 888mel, and TLR4-negative (TLR4(‒)) 928mel melanoma cells. Lipopolysaccharide (LPS), a TLR4 agonist, increased the proliferation of TLR4(+) melanoma cells but not of TLR4(‒) 928mel cells. The proliferation-inducing effect of LPS in 888mel cells was abolished by blockade of TLR4 signaling via treatment with short interfering RNA (siRNA) targeting TLR4 or myeloid differentiation primary response gene 88 (MyD88), a molecule downstream of TLR4. However, knockdown of TLR4 or MyD88 expression did not affect the LPS-induced proliferation of 501mel cells, suggesting that residual TLR4 signaling is sufficient to maintain cell proliferation. By contrast, LPS increased the migration of TLR4(+) melanoma cells, and this effect was substantially inhibited by TLR4 or MyD88 knockdown. Furthermore, TLR4 knockdown decreased cell migration even in the absence of LPS, suggesting the presence of an endogenous TLR4 ligand(s) in melanoma cells. TLR4 signaling may contribute to melanoma progression, and caution should be exercised when using TLR4 ligands as adjuvant therapy for cancer.

RNAi of the translation inhibition gene 4E-BP identified from the hard tick, Haemaphysalis longicornis, affects lipid storage during the off-host starvation period of ticks.

4E-BP, an eIF4E-binding protein, is well known as a cap-dependent translation inhibitor. Here, the 4E-BP homolog, Hl4E-BP, was isolated and identified from the hard tick Haemaphysalis longicornis. Hl4E-BP transcripts were ubiquitously expressed in the active stages, including the larvae, nymphs, and female adults, and the transcription levels were found to be higher in unfed than engorged ticks. In contrast, the expression levels of non-phosphorylated Hl4E-BP, which is a 13.4-kDa protein detected by the anti-recombinant Hl4E-BP antibody, were the highest in engorged ticks and significantly decreased progressively during the unfed starvation period of ticks. The functional role of Hl4E-BP as a metabolic brake was verified by histochemical observations on the lipid storage in midguts and fat bodies during the starvation period using ticks injected with dsHl4E-BP. The results indicate that Hl4E-BP is highly relevant to the lipid storage of ticks during the non-feeding starvation period. Our results suggest, for the first time, that Hl4E-BP may have a crucial role in the starvation resistance of ticks in an off-host condition via lipid metabolism control, although it was unclear whether Hl4E-BP might be involved in lipid synthesis regulation and/or lipid consumption inhibition.