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Macrophages internalize pathogens for intracellular degradation. An important part of this process is the phagosomal transport from the cell periphery to the perinuclear region. Biochemical factors are known to influence the fate of phagosomes. Here, we show that the size of phagosomes also has a strong influence on their transport. We found that large phagosomes are transported persistently to the nucleus, whereas small phagosomes show strong bidirectional transport. We show that dynein motors play a larger role in the transport of large phagosomes, whereas actin filament-based motility plays a larger role in the transport of small phagosomes. Furthermore, we investigated the spatial distribution of dyneins and microtubules around phagosomes and hypothesize that dynein and microtubule density differences between the nucleus-facing side of phagosomes and the opposite side could explain part of the observed transport characteristics. Our findings suggest that a size-dependent cellular sorting mechanism might exist that supports macrophages in their immunological roles.

Metastatic disease isolated to the liver is present at the time of diagnosis in 20-30% of patients with colorectal cancer. Only 10% of patients are eligible for resection. Systemic chemotherapy remains the primary treatment modality for such patients. The morbidity associated with regional chemotherapy is largely a result of the laparotomy required to place a hepatic arterial infusion pump in these debilitated patients. We discuss the main advantages of laparoscopic approach in comparison to both open procedure and percutaneous hepatic artery catheterization. From November 1993 to April 2004, 27 patients (16 males, 11 females) underwent laparoscopic placement of a hepatic artery catheter. The mean age was 64.9 years (46 to 82 years). 24 patients (88.8%) had bilobar disease precluding surgical resection of the liver metastases. There were four cases of non-colon cancers, all with liver metastases. LHAC alone averaged 45-55 minutes. Mean blood loss of 151 cc (20-300 cc). Postoperatively, 16 patients (59.2%) had hepatic intra-arterial chemotherapy in the recovery room as a preplanned protocol. Average hospital stay was 8.4 days (3-25 days). Median follow-up period of 8.1 months. 22 patients with residual hepatic disease, in whom chemotherapy was successfully instituted, showed regression of their metastases, in 18 patients, CEA had improved at their one-month follow-up visit. Three complications: one catheter thrombosis, one partial catheter occlusion and one eroded catheter into the duodenum one year after. In experienced hands, laparoscopic hepatic artery catheterization is a safe, feasible and minimally invasive technique for those patients with metachronous liver malignancies.

The use of prosthetic mesh has become the standard of care in the management of hernias because of its association with a low rate of recurrence. However, despite its use, recurrence rates of 1% have been reported in primary inguinal repair and rates as high as 15% with ventral hernia repair. When dealing with difficult recurrent hernias, the two-layer prosthetic repair technique is a good option. In the event of incarcerated or strangulated hernias, however; placement of prosthetic material is controversial due to the increased risk of infection. The same is true when hernia repairs are performed concurrently with potentially contaminated procedures such as cholecystectomy, appendectomy, or colectomy. The purpose of this study is to report our preliminary results on the treatment of recurrent hernias by combining laparoscopic and open techniques to construct a two-layered prosthetic repair using a four ply mesh of porcine small intestine submucosa (Surgisis, Cook Surgical, Bloomington, IN, USA) in a potentially infected field and a combination of polypropylene and ePTFE (Gore-Tex, W.L. Gore and Associates, Flagstaff, AZ, USA) in a clean field. From September 2002 to January 2004, nine patients (three males and six females) underwent laparoscopic and open placement of surgisis mesh in a two layered fashion for either recurrent incisional or inguinal hernias in a contaminated field. A total of eight recurrent hernia repairs were performed (five incisional, three inguinal) and one abdominal wall repair after resection of a metastatic tumor following open colectomy for colon carcinoma. Six procedures were performed in a potentially contaminated field (incarcerated or strangulated bowel within the hernia), two procedures were performed in a contaminated field because of infected polypropylene mesh, and one was in a clean field. Mean patient age was 56.4 years. The average operating time was 156.8 min. Operative findings included seven incarcerated hernias (four incisional and three inguinal), one strangulated inguinal hernia, and one ventral defect after resection of an abdominal wall metastasis for a previous colon cancer resection. In two of the cases, there was an abscess of a previously placed polypropylene mesh. All procedures were completed with two layers of mesh (eight cases with surgisis and one with combination of polypropylene/ePTFE). Median follow up was 10 months. Complications included two seromas, one urinary tract infection, two cases of atelectasis and one prolonged ileus. There were no wound infections. The average postoperative length of stay was 7.8 days. There have been no mesh-related complications or recurrent hernias in our early postoperative follow-up period. The use of a new prosthetic device in infected or potentially infected fields, and the two-layered approach shows promising results. This is encouraging and provides an alternative approach for the management of difficult, recurrent hernias.

Dinkmeyer, D., Dreikurs, R., Encouraging children to learn., Englewood Cliffs, N. J., Prentice-Hall, 1963. Gazda, G. M., Asbury, F. R., Balzer, F. J., Childers, W. C., Walters, R. P., Human relations development: a manual for educators., Boston, Allyn and Bacon, 1977, (2nd ed.

Purpose Meningiomas are the most frequently diagnosed intracranial neoplasms. Usually, they are treated by surgical resection in curative intent. Radiotherapy and stereotactic radiosurgery are commonly applied in the adjuvant setting in newly diagnosed atypical (CNS WHO grade 2), and anaplastic (CNS WHO grade 3) meningioma, especially if gross total resection is not feasible, and in recurrent cases. Conversely, the evidence for pharmacotherapy in meningioma is scarce. Methods The available literature of systemic treatment in meningioma was screened using PubMed, and ongoing clinical trials were explored using ClinicalTrials.gov. Results Classical cytotoxic agents, somatostatin analogs, and antihormone treatments have shown only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those targeting angiogenic signaling such as sunitinib and bevacizumab, have shown promising antitumoral activity in small phase 2 trials. Moreover, results of recent landmark studies on (epi-)genetic alterations in meningioma revealed potential therapeutic targets which are currently under investigation. These include inhibitors of mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling, and histone deacetylases. In addition, clinical trials evaluating immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently being conducted and early results suggest clinically meaningful responses in a subset of patients. Conclusions There is a paucity of high-level evidence on systemic treatment options in meningioma. However, interesting novel treatment targets have been identified in the last decade. Positive signals of anti-angiogenic agents, genomically targeted agents and immunotherapy in early phase trials should be confirmed in large prospective controlled trials.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC , YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC , YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers. Whole-exome sequencing of human brain metastases from lung adenocarcinoma uncovers new drivers by comparison of somatic alteration frequencies in brain metastasis cases to those in primary lung adenocarcinomas.

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes. Cholesterol is important for axonal myelination during development. Here the authors show that cholesterol levels are reduced in a cuprizone mouse model of multiple sclerosis and that dietary cholesterol supplementation enhances remyelination and recovery.

Antibody–drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood–brain or blood–tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.Antibody–drug conjugates (ADCs) have demonstrated efficacy in patients with various cancers, although their antitumour activity in the central nervous system (CNS) might be limited by the blood–brain barrier. In this Review, the authors describe the available clinical data emphasizing the heterogeneous activity of ADCs against primary or secondary brain tumours and ongoing clinical trials in this area. In addition, they discuss physical, biological and molecular determinants of the CNS activity of ADCs, as well as potential strategies to improve delivery of these agents to brain tumours.

In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.