Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Together with regulatory T cells (Tregs), tumor‐associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte‐derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD‐L1 and chemokines by CD163⁺ CD206⁺ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD‐L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD‐L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T‐cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.     

Providing Mental Health Services in the Primary Care Setting: the Experiences and Perceptions of General Practitioners at a New York City Clinic

Mental illness is a significant cause of disability worldwide, including here in the United States. Given the shortage of trained mental health professionals, a significant portion of patients needing care are managed in the primary care setting. Accountable Care Organizations (ACOs), for example, are seeking to improve the quality of care for this vulnerable population, but many are facing significant challenges relating to integration of new services. We sought to elucidate barriers faced by primary care practitioners (PCPs)—physicians, physician trainees and nurse practitioners—at a New York primary care clinic, which impede delivery of optimal care to those suffering from mental illness. The study was conducted with 32 PCPs in 2016–2017 at Mount Sinai Internal Medicine Associates in New York City. For the quantitative component of the study, a 54-item questionnaire was devised to assess their attitude, behavior and confidence in managing psychiatric patients. For the qualitative component, data was obtained from 3 open-ended questions. Responses were coded for salient themes. Analysis revealed a range of difficulties faced by PCPs. Overall, participants felt that the need to integrate mental health care into primary care was important, however they reported significant barriers in terms of lack of time, lack of resources, low confidence in treating more complex mental health conditions and difficulties with referring patient to mental health specialists. Despite a growing body of evidence that integration of mental health services in primary care leads to improved outcomes, addressing barriers to care will be key to ensuring feasibility of integration measures.     

Size and Composition of T-Cell Receptor δ (TCRD) Junctional Sequences Are Not Predictive of the Sensitivity of Clonospecific Oligonucleotides Designed for Detection of Minimal Residual Disease in Acute Lymphoblastic Leukemia

We characterized 168 junctional regions of T-cell receptor delta (TCRD) rearrangements from 116 children with acute lymphoblastic leukemia (ALL) (101 with precursor B-cell ALL, 15 with T-cell ALL). Application of 101 allele-specific oligonucleotide (ASO) probes representing 85 Vdelta2Ddelta3, 10 Ddelta2Ddelta3, 3 Vdelta1Jdelta1, 1 Vdelta3Jdelta1, and 2 Ddelta2Jdelta1 junctions for the detection of minimal residual disease (MRD) revealed detection levels of 10(-4) to 10(-6) leukemia cells in the vast majority of cases (93 of 101). Of interest was that neither the N, D, P (nontemplated, diversity, palindromic) content and length of the junctional regions nor the number of nucleotides deleted from the flanking V, D, or J (variable, diversity, joining) elements correlated with the sensitivity of ASO probes. These data indicated that in ALL TCRD rearrangements can serve as suitable tools for the detection of MRD irrespective of the specific composition of the junctional region.     

Cardiovascular risk factors associated with pulse pressure in a screened cohort in Okinawa, Japan.

We evaluated the association between pulse pressure (PP) and cardiovascular risk factors in a screened cohort. Individuals who were receiving medications for hypertension or heart disease, who had no ECG record, or who had a record of arrhythmia were excluded. In total, 8,508 subjects (5,299 men and 3,209 women; age range, 18 to 89 years) were studied. Subjects were divided into four PP classes: PP.1 (PP < or = 40 mmHg, n=2,127), PP.2 (40 < or = PP < or = 44 mmHg, n=2,127), PP.3 (44 < or = PP < or = 50 mmHg, n=2,127) and PP.4 (50 mmHg < or = PP, n=2,127). Multiple regression analysis was used for evaluating the association between PP and cardiovascular risk factor or lifestyle. In men, the regression coefficient was 0.27 for age, 2.50 for diabetes mellitus, 0.33 for uric acid, 0.20 for body mass index, 0.07 for heart rate, -0.83 for current smoking habit and 1.23 for habitual drinking. In women, the regression coefficient was 0.37 for age, 4.09 for diabetes mellitus, 0.42 for body mass index, 0.14 for heart rate, and 0.84 for habitual exercise. In both men and women, PP was significantly increased in association with an increase in the number of risk factors (diabetes mellitus, obesity, current drinking status, heart rate, and hyperuricemia). In conclusion, higher PP was associated with cardiovascular risk factors. These associations were similar in both men and women.     

Galpha(12/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy

In neonatal cardiomyocytes, activation of the G(q)-coupled alpha(1)-adrenergic receptor (alpha(1)AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK). Here, we show that JNK activation is essential for alpha(1)AR-induced hypertrophy, in that alpha(1)AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate alpha(1)AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. alpha(1)AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Galpha(q), Galpha(12), and Galpha(13). JNK activation was also inhibited by the Galpha(q/11)- or Galpha(12/13)-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein-coupled receptor kinase 2, a polypeptide that sequesters Gbetagamma. alpha(1)AR-induced hypertrophic responses were inhibited by Galpha(q/11)- and Galpha(12/13)-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein-coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of Galpha(12) and Galpha(13) but not by Galpha(q). Our findings suggest that alpha(1)AR-induced hypertrophic responses are mediated in part by a Galpha(12/13)-Rho-JNK pathway, in part by a G(q/11)-JNK pathway that is Rho independent, and in part by a Gbetagamma pathway that is JNK independent.     

Organ Correlation in IgG4-Related Diseases

IgG4-related disease (IgG4-RD) is a potentially multiorgan disorder. In this study, clinical and serological features from 132 IgG4-RD patients were compared about organ correlations. Underlying pathologies comprised autoimmune pancreatitis (AIP) in 85 cases, IgG4-related sclerosing cholangitis (IgG4-SC) in 12, IgG4-related sialadenitis (IgG4-SIA) in 56, IgG4-related dacryoadenitis (IgG4-DAC) in 38, IgG4-related lymphadenopathy (IgG4-LYM) in 20, IgG4-related retroperitoneal fibrosis (IgG4-RF) in 19, IgG4-related kidney disease (IgG4-KD) in 6, IgG4-related pseudotumor (IgG4-PT) in 3. Sixty-five patients (49%) had multiple IgG4-RD (two affected organs in 36 patients, three in 19, four in 8, five in 1, and six in 1). Serum IgG4 levels were significantly higher with multiple lesions than with a single lesion (P<0.001). The proportion of association with other IgG4-RD was 42% in AIP, the lowest of all IgG4-RDs. Serum IgG4 level was lower in AIP than in other IgG4-RDs. Frequently associated IgG4-RDs were SIA (25%) and DAC (12%) for AIP; AIP (75%) for IgG4-SC; DAC (57%), AIP (38%) and LYM (27%) for IgG4-SIA; AIP (26%) and LYM (26%) for IgG4-DAC; SIA (75%), DAC (50%) and AIP (45%) for IgG4-LYM; SIA (58%), AIP (42%) and LYM (32%) for IgG4-RF; AIP (100%) and SIA (67%) for IgG4-KID; and DAC (67%) and SIA (67%) for IgG4-PT. Most associated IgG4-RD lesions were diagnosed simultaneously, but IgG4-SIA and IgG4-DAC were sometimes identified before other lesions. About half of IgG4-RD patients had multiple IgG4-RD lesions, and some associations were seen between specific organs.

Graphical Abstract

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A case of synchronous primary lung cancer with hamartoma]

We present a case of a synchronous primary lung cancer adjacent to a hamartoma. In a 48-year-old man, a nodular shadow was found in the right middle lung field in 1990, and had grown slowly for 10 years. Another mass shadow was detected in the right upper lung field in 2000. The patient was admitted to our hospital for further examination of these abnormal shadows. Bronchoscopic examination revealed, in the right upper lobe, a poorly differentiated adenocarcinoma of clinical stage IIIB. Neoadjuvant chemotherapy followed by pneumonectomy was performed. The microscopic findings for the tumor resected from the right S2 showed poorly differentiated adenocarcinoma and those for the other, in the right S3, showed chondromatous hamartoma. Some 50 reports of lung cancer in parents with a chondromatous hamartoma have appeared in the literature. Most of these cases have some common features as follows: 1) men past middle age, 2) adenocarcinoma, and 3) lung cancer and chondromatous hamartoma present in the same lobe. The present case had all of these features, and may assist in the understanding of the process of development of lung cancer adjacent to a hamartoma.     

Myocardial bridging increases the risk of coronary spasm

BACKGROUND: Myocardial bridging (MB) has been associated with cardiac events. Whether coronary spasm is one factor contributing to those events is unknown. HYPOTHESIS: This study investigated whether the likelihood of coronary spasm is increased in patients with MB. METHODS: A spasm-provocation test was performed by infusing acetylcholine into the left coronary artery in 114 Japanese patients with chest pain. The test result was defined as positive when the diameter of the coronary artery was reduced by > or = 50% and ST-segment changes were documented. Myocardial bridging was defined as a > 15% reduction in coronary arterial diameter during systole after intracoronary injection of nitroglycerin. RESULTS: Myocardial bridging was identified in 41 patients (36%) and was located in the mid-segment of the left anterior descending coronary artery (LAD) in all patients. Patients with MB experienced coronary spasm more frequently than patients without MB (MB+: 73%; MB-: 40%, p = 0.0006). Furthermore, among patients with a positive spasm-provocation test, coronary spasm occurred more frequently in the mid-segment of the LAD in patients with MB than in those without MB (MB+: 73%; MB-: 45%, p = 0.0259). Multivariate regression analysis demonstrated that MB was a predictor of coronary spasm (odds ratio: 3.478, p = 0.0088). CONCLUSIONS: These results suggest that MB increases the risk of coronary spasm and that coronary spasm may be the proximate etiology of cardiac events associated with MB.     

An autopsy case of desmoplastic malignant mesothelioma]

On November 15, 2000, a 60-year-old man was admitted to our hospital with progressive dyspnea and right chest pain. He had a 40-year history of occupational asbestos exposure, which began when he was 20 years old. On admission, his chest radiographs showed pleural effusion on the right side, and asbestos bodies were detected in his sputum. Neither a cytological examination of the pleural effusion nor a histological examination of the pleura by percutaneous pleural biopsy revealed malignant cells. In addition, we could not find any other cause for the pleural effusion (such as tuberculosis, collagen disease, or heart failure). In May 2001, the patient also developed pleural thickening and pain in the right hypochondrium, and he was readmitted to our hospital on May 21, 2001. On readmission, an enhanced abdominal CT showed multiple liver tumors, and percutaneous pleural and liver biopsies were performed. The histological findings in the pleura and liver specimens revealed hypocellular collagen tissues without malignant cells. Thus, we could not determine the main cause either of the pleural effusion or of the patient's disease. However, his condition rapidly deteriorated, and he died on August 12, 2001. At the autopsy, bilateral pleural thickening, predominantly on the right side, and invasion of the lungs were observed. The histological findings in the pleural and hepatic tissues revealed hypocellular collagen fibers with a striate pattern and areas of neoplastic spindle cells. He was diagnosed as having malignant desmoplastic mesothelioma with liver metastasis. Cases of malignant desmoplastic mesothelioma have rarely been reported in Japan.