Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.

Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.

Identification of the fate and regenerative mechanism of zebrafish melanocyte progenitor cells and melanocytes after laser-induced pigment ablation.

BACKGROUND AND OBJECTIVES: Lasers are known to be the most effective treatment modality for pigmentary skin diseases. However, melanocytes and melanin pigment often recur or leave post-inflammatory hyperpigmentation after the laser procedure. Studies have reported on the role of progenitor cells in pigment cell regeneration, which can be constantly replenished through mitosis. However, the response of unpigmented melanocyte progenitor cells to laser treatment is poorly understood. In this study, we used adult zebrafish skin as the melanocyte regenerative system and examined the response of melanocyte progenitor cells to laser photothermolysis. MATERIALS AND METHODS: The two groups of adult zebrafish were irradiated with 1064 nm wavelength laser system of Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with 0.3 or 0.7 J·cm-2 . We compared the regeneration of pigment at different energy levels by measuring new melanocyte counts and pigment area. We traced and quantitatively compared the melanocyte lineage cells by immunohistochemical staining using specific markers such as sox10, mitfa, and dct during the regeneration process. Three repetitive laser ablations were also held to test the postinflammatory hyperpigmentation. RESULTS: After the laser ablation of melanocytes, most of the new melanocytes appeared between Days 5 and 10. In high-energy irradiation of 0.7 J·cm-2 , the unpigmented mitfa-expressing cells showed significant decrease (p < 0.05) and showed delay in the differentiation process of melanocyte lineage cells. After repeated laser irradiation, hyperpigmentation did not appear and the final recovery ratio of the pigmented area was 87.5% and 75.3% at the 0.3 and 0.7 J·cm-2 energy levels, respectively. CONCLUSION: We suggest that laser treatment overcoming the recurrence should be planned based on the adequate energy level targeting the melanocyte progenitor cells. High-energy irradiation may induce apoptosis of progenitor cells and delay their process of differentiation. Short-term repetitive sessions of laser therapy can reduce the pigmentation in the long-term observation.

A Case of Seizure Revealing Fahr's Syndrome with Primary Hypoparathyroidism.

BACKGROUND Idiopathic basal ganglia calcification, also known as Fahr's disease or Fahr's syndrome, is a rare neurological disorder characterized by abnormal calcified deposits in the basal ganglia. Here, we report a case of Fahr's syndrome with calcification of the basal ganglia due to hypoparathyroidism in a patient with seizures. CASE REPORT A 52-year-old male patient visited our clinic with seizures. Brain computed tomography (CT) showed bilateral symmetrical calcifications in cerebellar white matter, the corpus striatum, the posterior thalami, and the centrum semiovale of both cerebral hemispheres. He had symptoms of hypocalcemia and low parathyroid hormone levels. The patient was diagnosed with Fahr's syndrome due to primary hypoparathyroidism. He underwent calcium supplementation and calcifediol treatment. His symptoms improved, and he was discharged from the hospital. CONCLUSIONS In patients with hypocalcemia accompanied by parathyroid dysfunction, neurological examination and CT should be performed to confirm abnormal intracranial calcification.

Comparative study of dual-pulsed 1064 nm Q-switched Nd:YAG laser and single-pulsed 1064 nm Q-switched Nd:YAG laser by using zebrafish model and prospective split-face analysis of facial melasma.

BACKGROUND: Recently dual-pulsed low-fluence 1064-nm Q-switched Nd:YAG (QSNY) laser has been developed for reducing complication during melasma treatment. OBJECTIVE: Comparison of the efficacy and safety between dual-pulsed mode and single-pulsed mode for the treatment of melasma. MATERIALS AND METHODS: In preclinical study, adult zebrafish were irradiated with dual-pulsed and single-pulsed mode. Changes of melanophore and cell death were assessed. In split-face clinical study, dual-pulsed and single-pulsed mode were irradiated on the left and right side of the face, respectively. L* value, clinical digital photos, modified Melasma Area and Severity Index (MASI) scores, and side effects were measured. RESULTS: As compared to single-pulsed mode and dual-pulsed mode with longer intervals, zebrafish melanophore was cleared quickly at dual-pulsed mode with 80-µsec interval and 0.3 J/cm2 fluence. Dual-pulsed mode showed the least regeneration of melanophore at 4 weeks after irradiation and no cell death was observed with 80-µsec interval. Both pulse modes improved melasma significantly but modified MASI score and L* value were not significantly different between each other. Lesser pain and shorter duration of post-laser erythema were observed with dual-pulsed mode. CONCLUSION: Dual-pulsed mode was as effective as single-pulsed mode for the treatment of melasma and revealed less side effects.

Decursin in Angelica gigas Nakai (AGN) Enhances Doxorubicin Chemosensitivity in NCI/ADR-RES Ovarian Cancer Cells via Inhibition of P-glycoprotein Expression.

Angelica gigas Nakai (AGN, Korean Dang-gui) is traditionally used for the treatment of various diseases including cancer. Here, we investigated multidrug-resistant phenotype-reversal activities of AGN and its compounds (decursin, ferulic acid, and nodakenin) in doxorubicin-resistant NCI/ADR-RES ovarian cancer cells. Our results showed that a combination of doxorubicin with either AGN or decursin inhibited a proliferation of NCI/ADR-RES cells. These combinations increased the number of cells at sub-G1 phase when cells were stained with Annexin V-fluorescein isothiocyanate. We also found that these combinations activated caspase-9, caspase-8, and caspase-3 and increased cleaved PARP level. Moreover, an inhibition of P-glycoprotein expression by either AGN or decursin resulted in a reduction of its activity in NCI/ADR-RES cells. Therefore, our data demonstrate that decursin in AGN inhibits doxorubicin-resistant ovarian cancer cell proliferation and induces apoptosis in the presence of doxorubicin via blocking P-glycoprotein expression. Therefore, AGN would be a potentially novel treatment option for multidrug-resistant tumors by sensitizing to anticancer agents. Copyright © 2016 John Wiley & Sons, Ltd.

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

Combined intense pulsed light and Er:YAG laser treatment of congenital melanocytic nevus.

Congenital melanocytic nevi (CMN) are benign nevomelanocytic proliferations that are present at birth. CMN are commonly classified according to their size and the management of CMN is diverse, including excision, dermabrasion and laser treatment. Several studies have shown the effectiveness of laser therapy for CMN in cosmetically sensitive and anatomically critical areas. In the present case, combination treatment with intense pulsed light (IPL) and erbium:yttrium-aluminum-garnet (Er:YAG) laser was used, and its effectiveness was evaluated. A 56-year-old man with a CMN on the left malar area was treated with combined IPL and Er:YAG laser treatment once monthly. After ten sessions of treatment, the lesion showed improvement leaving only a grayish hue. Thus, we report a case of CMN on face that was successfully treated with combined IPL and Er:YAG laser treatment.

Lack of medial prefrontal cortex activation underlies the immediate extinction deficit.

We conducted a series of experiments to investigate the neural basis of the immediate extinction deficit, the lack of extinction when the interval between fear memory acquisition and extinction is short. In experiment 1, rats were given extinction training composed of 15 conditioned stimuli (CSs) either 15 min (immediate extinction: I-EXT) or 24 h (delayed extinction: D-EXT) after five tone-shock pairings. In the retention test performed 48 h after conditioning, I-EXT group exhibited significantly higher freezing than D-EXT group. In experiment 2, functional activation in the medial prefrontal cortex (mPFC) was detected using c-fos immunoreactivity. The number of Fos-positive neurons in the mPFC was significantly lower in I-EXT group than in D-EXT group. In experiment 3, rats received immediate extinction with microstimulation of the infralimbic region (IL) of the mPFC, either contingently paired or unpaired with the CS. In a subsequent retention test, the paired stimulation group exhibited decreased freezing relative to the unpaired stimulation group. Together, our results suggest that the immediate extinction deficit may be linked to the lack of neuronal activity in the IL.

Effects of myofascial-meridian stimulation therapy (mmst) on shoulder pain.

Fifty patients with shoulder pain were classified into two groups according to the type of pain: a capsular-pattern group (N = 22) and a non-capsular-pattern group (N = 28). Both groups received myofascial-meridian stimulation therapy four times in two weeks. After therapy, the pain level was significantly lower in the capsular-pattern than in the non-capsular-pattern group. The capsular-pattern group showed a nonsignificant trend toward greater range of motion than the non-capsular-pattern group. These data suggest that myofascial-meridian stimulation therapy might be useful as a new treatment to reduce pain and increase range of motion in patients with shoulder pain.