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In this clinical and skin biopsy study, we aimed to investigate whether fibromyalgia-associated small-fiber pathology (SFP), consisting of an intraepidermal nerve fiber loss, implies damage of dermal autonomic nerve fibers and how this damage is associated with autonomic symptoms that patients with fibromyalgia syndrome experience. Using skin biopsy, we investigated intraepidermal nerve fiber density, piloerector muscle, and sweat gland nerve fiber density (SGNFD) in 138 participants, that is, 58 patients with fibromyalgia syndrome, 48 healthy subjects, and 32 patients with small-fiber neuropathy. In patients with fibromyalgia-associated SFP, we also investigated how the different skin biopsy variables correlated with autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 questionnaire. We found that in patients with fibromyalgia-associated SFP, the piloerector muscle and SGNFD were lower than that in healthy subjects. However, the autonomic small-fiber damage had no correlation with autonomic symptoms severity. In patients with SFP, the intraepidermal, piloerector muscle, and SGNFD were higher than that in patients with small-fiber neuropathy. Our clinical and skin biopsy study shows that patients with fibromyalgia have a reduction of dermal autonomic small fibers paralleling the intraepidermal nerve fiber loss, thus indicating that SFP also implies autonomic small nerve fiber damage. However, the autonomic small-fiber damage we found had no correlation with the severity of autonomic symptoms, and thus its clinical impact is still undetermined.

Illuminate Shrubs, Bushes, and Hedges BEST LIGHTS FOR THE JOB: NET WHY THEY WORK/To illuminate shrubs, bushes, and hedges, think net lights. The larger C9 lights look like traditional holiday lights and are used on rooflines and for ground-stake lighting. [Extracted from the article]

Neuropathic pain, defined as pain arising as a consequence of a lesion or disease affecting the somatosensory nervous system, requires precise diagnostic assessment. Different diagnostic tools have been devised for the diagnosis of neuropathic pain. This review offers insights into the diagnostic accuracy of screening questionnaires and different tests that investigate the somatosensory nervous system, in patients with suspected neuropathic pain. Thus, it illustrates how these tools can aid clinicians in accurately diagnosing neuropathic pain.

Set the frame in front of the doorway and fasten it to the timber frame foundation with four 3½-in. structural screws. INSTALL FOUNDATION AND WALLS Set the timber frame foundation on the ground and use a 4-ft. level to confirm that it's level across its width and length. Stand the wall on the timber frame foundation, aligning the sole plate flush with the outer edge of the 4x6 foundation timber [13]. FRAME THE WALLS All four walls of the greenhouse are framed with 2x4s. [Extracted from the article]

IF YOU DON'T HAVE A LOT OF SPACE: BANTAMS Bantams can be one-fifth the size of a typical chicken, ideal for those with less coop space. There's a small fold-down door on one end to let the chickens out when you'd like, and another door cut into the plywood roof gives you access to the roosting loft when you need to gather eggs. FEATURES More than 13 million homeowners raise backyard chickens, according to the U.S. Department of Agriculture, and that number is expected to grow over the next several years. [Extracted from the article]

Doors Shed doors aren't weatherproof and they provide little security, so replace the existing door with an exterior-grade entry door. YOUR SHED INSPECTION CHECKLIST FOUNDATION For sheds on concrete blocks, check that… Each block supports the shed (opposed to shifted/sunk) Each block is free of cracks. ROT Check the following for rot: Floor frame/ floor deck Perimeter band joists/floor joists Corner posts/ poles (in pole-barn sheds) Wall studs/ wall sheathing/ siding Ceiling joists/ collar ties/rafters Plywood roof sheathing/roof shingles. [Extracted from the article]

Install a Pressure Booster // When all other methods have failed, hire a licensed plumbing contractor or well contractor to install a water-pressure booster pump. WHEN SHOWERHEADS IN YOUR HOME ARE WEAK, water dribbles out of faucets, and the washing machine takes forever to fill, the problem could be low water pressure. With homes supplied by a well, you may be able to adjust the cut-in and cut-out pressure for the pressure tank and well pump, increasing the pressure of the water supply in the process. [Extracted from the article]

Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFRand HER2are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFRexon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFRand HER2exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

AimsNeurotrophic Tropomyosin Kinase Receptor 1 (NTRK1) gene encodes for the protein Tropomyosin-related kinase A (TRKA). Deregulated activity of TRKA has been shown to have oncogenic potential. We present here the results of an immunohistochemical (IHC) observational cohort study of TRKA expression together with gene copy number (GCN) assessment in various solid tumours.MethodsFormalin-fixed, paraffin-embedded consecutive samples of different tumour types were tested for TRKA expression. Samples showing TRKA IHC staining in at least 10% of cells were analysed by fluorescence in situ hybridisation to assess NTRK1gene rearrangements and/or individual GCN gain. All patients underwent this molecular assessment within the phase I ALKA-001 clinical trial.Results1043 samples were tested and annotation for histology was available in 1023. Most of the samples were colorectal adenocarcinoma (CRC) (n=550, 52.7%) and lung adenocarcinoma (n=312, 29.9%). 24 samples (2.3%) were biliary tract carcinoma (BTC). Overall, 17 (1.6%) samples were characterised by TRKA IHC expression (four weak, eight moderate, five strong): 9/17 lung adenocarcinoma, 3/17 CRC, 3/17 BTC, 1/17 thyroid cancer and 1/17 cancer of unknown primary. Of these, 1/17 with strong TRKA IHC staining displayed NTRK1gene rearrangement and 15/17 NTRK1GCN gain by FISH. No correlation was found between intensity of TRKA IHC staining and number of copies of NTRK1.ConclusionsTRKA expression can be found in 1.6% of solid tumours and can be paralleled by NTRK1gene rearrangements or mostly GCN gain. The prognostic and translational therapeutic impact of the latter remains to be established.

ObjectiveMutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).DesignGenome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.ResultsMethylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1%and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.ConclusionThis five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.

Neuropathic pain is a chronic condition representing a significant burden for patients, society, and healthcare systems. The prevalence of neuropathic pain in the general population has been estimated at 7–8% and is expected to increase in the future. Neuropathic pain differs from nociceptive pain and requires a different therapeutic approach; and the management of neuropathic pain is complicated and challenging. This chapter discusses clinical practice guidelines for neuropathic pain and their usefulness in clinical practice. Funding:Pfizer, Italy.

Neuropathic pain develops when the somatosensory nervous system is affected by a lesion or disease. Diagnostic tests aimed at assessing somatosensory afferent pathway damage are therefore useful for diagnosing neuropathic pain. Neuropathic pain manifests with a range of different symptoms such as ongoing burning pain, squeezing or pressure pain, paroxysmal electric shock-like sensations, stabbing pain, or mechanical dynamic allodynia. The various types of neuropathic pain are associated with different underlying nerve fiber abnormalities. This article summarizes the available methods of somatosensory afferent pathway assessment and discusses the potential pathophysiology underlying the most representative neuropathic pain types, i.e., ongoing burning pain, paroxysmal pain, and mechanical dynamic allodynia. Funding:Pfizer, Italy.

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitroand impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitroand in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.

Malignant Pleural Mesothelioma (MPM) is an aggressive disease characterized by a dismal prognosis, mainly due to late diagnosis. To date, there are very few treatment options available and the refractoriness to the majority of therapeutic strategies, leading to consider MPM a relevant problem in public health. Therefore, the identification of novel prognostic markers and alternative therapeutic strategies remain a top priority. Several efforts have been made in this direction and to date a number of studies have investigated the role of microRNA as biomarkers in MPM, identifying the potential prognostic role of miR-29c* and miR-31. Very recently, the first microRNA signature able to discriminate poor or and good prognosis of MPM patients underwent surgery has been published. Very interestingly, several microRNA such as miR-1, miR-16, and miR-34b/c have been identified as potential therapeutic agents. Indeed, the forced expression of these microRNA resulted in anti-tumor effects both in vitro and in vivo. Besides, the introduction of microRNA mimic, some agents such as EphrinA1 and Onconase, seemed to exert anti-tumor effects through specific microRNA. Moreover, microRNA have also been reported to play a role in chemoresistance enhancing the sensitivity to specific drug such as pemetrexed. In this review the most relevant and updated data about the role of microRNA as prognostic markers and therapeutic agents in MPM will be presented, opening new avenues towards improved management of this aggressive disease.

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2testing protocols and ERBB2scoring criteria were used to centrally screen for ERBB2-positive KRASwild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRASwild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

Introduction:Immunotherapy has become a promising approach for the treatment of NSCLC. In order to stimulate the host immune system against tumour antigens, several cancer vaccines have been generated and evaluated. Belagenpumatucel-Lis a whole tumour cell vaccine expressing the antisense strand of the TGF-β2 gene.Areas covered:The purpose of this article is to review the most relevant findings of clinical trials testing belagenpumatucel-L in advanced NSCLC patients.Expert opinion:Although the Phase III trial investigating belagenpumatucel-L in stage III/IV patients did not meet its primary end point, a survival benefit was observed in several subgroups of patients. Further studies are needed in order to select patients who may benefit from this vaccine.

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related death worldwide. Based on the patient’s stage of disease, treatment options include surgery, radiotherapy, and chemotherapy. Although chemotherapy remains the main therapeutic approach for advanced NSCLC, targeted therapy represents a good chance of treatment for this subgroup of patients. Currently this approach is based on previous evaluation of clinically relevant mutations and the Sanger sequencing is the main approach to assign mutational status and to guide the appropriate treatment; however this tool is characterized by a low sensitivity. Recently, the advent of next-generation sequencing (NGS) has dramatically revolutionized the molecular knowledge of cancer by increasing the feasibility and possibility to sequence DNA ranging from large scale studies to targeted regions. This review reports an overview of different applications of the NGS as novel approach to study NSCLC, thereby providing information about mutational spectrum of this cancer in order to identify novel targetable mutations and to predict the emergence of drug resistance. All studies demonstrated several advantages of this approach over the traditional tools. In particular the NGS was also able to reveal mutations in low percentage, and to screen the mutational status of different critical samples such as biopsies, cytological samples and circulating plasma DNA, offering innovative diagnostic opportunities. Despite several problems have to be overcome toward the personalized therapy, the NGS represents a highly attractive system to identify mutations improving the outcome of patients with this deadly disease.

After removal of an ovarian mass in a 43-year-old woman, a struma ovarii was diagnosed. Within this teratoma, a papillary thyroid cancer was found. The tumor was negative for BRAF, NRAS, KRAS, PIK3CA and c-KIT mutations on molecular analysis. Thyroid function and morphology were normal. Thyroidectomy, L-T4 TSH-suppressive therapy and rhTSH-induced radioiodine ablation were performed. So far, the follow-up has been favorable. This is the first case of thyroid cancer in a struma ovarii in which mutations of PIK3CA exons 9 and 20, and c-KIT exons 9, 11 and 13 have been evaluated and the third in which ablation has been performed under rhTSH. The prognosis of patients with thyroid cancer in a struma ovarii is generally poor. In our patient, as in those who undergo ablative radioactive iodine therapy, this was not the case.

Introduction:Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib(AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer.Areas covered:We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients.Expert opinion:Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment.

Introduction:Originally formulated as an intravenous (i.v.) agent, vinorelbineis also currently available as an oral chemotherapeutic agent. Oral vinorelbine has demonstrated significant activity in different settings for NSCLC, including adjuvant treatment for resected disease, concurrent chemoradiation for locally advanced NSCLC and palliative chemotherapy for recurrent/metastatic NSCLC, as part of combination schedules or as a single-agent treatment.Areas covered:The authors explored the available data describing the use of oral vinorelbine in NSCLC. PubMed articles and abstracts presented at international conferences were analysed, and relevant trials were reported and discussed. Specific settings, including the treatment of elderly and unfit patients and metronomic schedules including oral vinorelbine, were evaluated. Available pharmacoeconomic data were also assessed.Expert opinion:Oral vinorelbine is an appealing agent, particularly as part of combination regimens containing platinum derivatives, although it can have a role as a single-agent treatment as well. Its safety profile is generally favourable and its route of administration is generally preferred by patients receiving chemotherapy. Compared to i.v. vinorelbine and other antineoplastic agents, oral vinorelbine has been reported to be advantageous in terms of cost savings.

Introduction:Despite recent advances with new chemotherapeutic agents and target therapies, the prognosis of NSCLC remains poor. Recent results from clinical trials of immunotherapeutic agents, especially with immune checkpoint inhibitors, make this approach very exciting in NSCLC. Ipilimumabis a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 that is able to stimulate the antitumour immune response by promoting T-cell activation.Areas covered:We have reviewed the literature and have described the most important results obtained with ipilimumab in NSCLC in recent trials with a specific focus on its peculiar toxicity profile and pattern of response. Trials ongoing with ipilimumab are also reported.Expert opinion:The results from clinical trials with ipilimumab are promising. Some important issues in the near future will be to identify prognostic and predictive biomarkers to select patients who could benefit from this drug. Further studies are warranted to understand how to combine ipilimumab with other anticancer strategies.

Introduction:The inhibition of the epidermal growth factor receptor (EGFR) through tyrosine kinase inhibitors (TKIs) represents an effective strategy for EGFR-mutated NSCLC. Afatinibis an irreversible erythroblastosis oncogene B (ErbB) family blocker, able to inhibit the kinase domains of EGFR, HER2 and HER4, and the transphosphorylation of ErbB3 that has recently been approved in the United States for the first-line treatment of EGFR-mutated NSCLC and in Europe and Japan for the treatment of EGFR-mutated TKI-naive patients.Areas covered:The authors analyzed the pharmacology and the clinical activity of afatinib in NSCLC through a review of the literature. Trials exploring different settings have been reported, including LUX-Lung 3 and LUX-Lung 6, where the drug achieved better outcomes in terms of response rate, progression-free survival and quality of life compared with chemotherapy. The main toxicities of afatinib are gastrointestinal and skin-related adverse events.Expert opinion:Afatinib showed remarkable efficacy as a first-line treatment in the presence of common EGFR mutations. Afatinib showed some activity in NSCLC with acquired resistance to EGFR TKIs, although, currently, its efficacy after the failure of erlotinib or gefitinib has not been clearly stated. Direct clinical data comparing the activity and tolerability of different inhibitors are still needed.

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.

The first screw eye is 1 in. from the end of the header, the second screw eye is 12 in. from the first one, and the third screw eye is positioned 18 in. from the second screw eye. To secure the shades in the middle of the pergola, I drilled 5/32-in.-dia. pilot holes into the inside ends of the dowels and then twisted in 1-in.-dia. screw eyes. Next, I drilled 3/8 -in.-dia. holes into the deck directly below the screw eyes, and then tapped in ¼-20 threaded metal inserts. [Extracted from the article]

Then cut the cabinet base from ¾-in. plywood, and the cabinet back from ¼-in. plywood. I installed three shelves and spaced the top two 10 in. apart, and the lower shelf about 13 in. above the cabinet base, resulting in four storage compartments. ASSEMBLE THE CABINET Apply carpenter's glue to the six shelf dadoes, and to the rabbet joints cut into the top of the side pieces. [Extracted from the article]

Neuropathic pain—that is, pain arising directly from a lesion or disease that affects the somatosensory system—is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.

Introduction:Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. Although advanced NSCLC is still incurable, various anti-neoplastic agents have become available for the treatment of this disease. Pemetrexed, a multi-target folate antagonist, has improved the survival of non-squamous NSCLC patients. Currently, pemetrexed is approved for first-line treatment in combination with a platinum derivate, for second-line treatment as a single agent and, more recently, as maintenance treatment after first-line chemotherapy.Areas covered:The authors analyzed the state of the art of pemetrexed through a review of the literature. Clinical trials and meta-analyses involving pemetrexed in NSCLC were evaluated. Pemetrexed improved survival of non-squamous NSCLC in first-line, maintenance, and second-line treatments; this benefit is limited to non-squamous histology. Because pemetrexed has become part of the standard of care, current clinical trials are designed to compare it to other investigational combinations. Limited data on resectable disease are available, and additional clinical trials are being conducted.Expert opinion:Pemetrexed has shown effectiveness and a favorable toxicity profile. Histology-driven indications and the relationship of pemetrexed with thymidylate synthase expression suggest that a more precise definition of predictive biomarkers could be further investigated.

Introduction:Non-small cell lung cancer (NSCLC) is one of the main causes of cancer-related deaths worldwide. Although new therapies have become available, innovative treatments are still needed for advanced disease. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), enhances the immune response against the tumor mass and has been proven effective against malignant melanoma.Areas covered:The authors explored the role of ipilimumab in NSCLC using a literature review. The clinical trials involving ipilimumab for lung cancer have shown progression-free survival (PFS) benefits. The use of ipilimumab is related to unusual adverse events resulting from increased or excessive immune activity. Because ipilimumab shows unique response patterns, more suitable criteria known as immune-related response criteria (ir-RC), different from RECIST and WHO criteria, are required.Expert opinion:Although NSCLC is not known as an immunogenic-mediated malignancy, in the past few years, the authors have observed an increasing interest in the development of therapies able to modulate the immune response including vaccines and non-specific immunoregulatory drugs (such as ipilimumab). Ipilimumab may become a new, powerful strategy for the management of NSCLC patients. Further investigation is needed to confirm the optimal treatment schedule and determine the potential predictors of response to the CTLA-4 blockade.

We assessed the effect of palmitoylethanolamide (PEA) on pain and nerve function in patients with chemotherapy-induced painful neuropathy, in 20 patients undergoing thalidomide and bortezomib treatment for multiple myeloma. All patients were evaluated before and after a two-month treatment with PEA 300 mg BID using pain and warmth thresholds; blinded examiners measured motor and sensory nerve fibre function and laser-evoked potentials. Although no variables returned to normal values, pain and all neurophysiological measures - assessing Aα, Aβ, and Aδ fibres - significantly improved (P < 0.05). In contrast, warmth thresholds, assessing unmyelinated afferents, remained unchanged (P 0.50). Although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures indicate that PEA exerted a positive action on myelinated fibre groups. PEA, possibly by moderating mast cell hyperactivity, relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function.

Introduction: Multiple sclerosis (MS) is an inflammatory, demyelinating, central nervous system disease that frequently causes pain.Areas covered: This article reviews the current literature and describes the therapeutic options for treating MS-related pain. The reader will be provided with current, evidence-based knowledge about the treatment of MS-related pain, and the review will take a practical approach to the various drugs for treating pain, including starting dose, titration and side effects.Expert opinion: Only cannabinoids have been assessed in randomized, controlled trials. Because of the concern regarding the risk of abuse and psychiatric adverse events, published guidelines as well as expert recommendations suggest using them as second-line therapy only. Hence, current treatment should be based on the general principles for treating peripheral neuropathic pain, taking into account drug-induced adverse effects.

Oral potentially malignant lesions (OPMLs) with dysplasia and aneuploidy are thought to have a high risk of progression into oral squamous cell carcinomas (OSCCs). Non-dysplastic “oral distant fields” (ODFs), characterized by clinically normal appearing mucosa sited at a distance from co-existing OPMLs, and non-dysplastic OPMLs may also represent an early pre-cancerous state. ODFs, OPMLs without and with dysplasia and OSCCs were investigated by high resolution DNA content flow cytometry (FCM). ODFs and OPMLs without dysplasia were DNA aneuploid respectively in 7/82 (8.5%) and 25/109 (23%) cases. “True normal oral mucosa” and human lymphocytes from healthy donors were DNA diploid in all cases and were used as sex specific DNA diploid controls. Dysplastic OPMLs and OSCCs were DNA aneuploid in 12/26 (46%) and 12/13 (92%) cases. The DNA aneuploid sublines were characterized by the DNA Index (DI≠1). Aneuploid sublines in ODFs and in non-dysplastic and dysplastic OPMLs were near-diploid (DI<1.4) respectively in all, 2/3 and 1/3 of the cases. DNA aneuploid OSCCs, instead, were characterized prevalently by multiple aneuploid sublines (67%), which were commonly (57%) high-aneuploid (DI≥1.4). DNA near-diploid aneuploid sublines in ODFs and OPMLs appear as early events of the oral carcinogenesis in agreement with the concept of field effect. Near-diploid aneuploidization is likely to reflect mechanisms of loss of symmetry in the chromosome mitotic division. High DNA aneuploid and multiple sublines in OPMLs with dysplasia and OSCCs suggest, instead, mechanisms of “endoreduplication” of diploid and near-diploid aneuploid cells and chromosomal loss. High resolution DNA FCM seems to enable the separation of subsequent progression steps of the oral carcinogenesis.

The contribution of the host's circulating progenitor cells after implantation of mesenchymal stem cells (MSC)/bioscaffold combinations for repairing bone defects has not been elucidated, although this issue affects the clinical application of the tissue engineering approach. We implanted blocks of hydroxyapatite loaded with murine MSCs into syngenic, allogenic, and immunocompromised recipients. After 8 weeks, we found that bone tissue was formed in syngenic and immunocompromised animals. The implanted cells appeared pivotal in the early stages of tissue development, but cells of the recipient's origin finally made bone. In this system, osteoprogenitors migrated from the recipient to the implant, whereas the implanted cells left the scaffold and entered the circulatory flow. We observed rapid destruction of implanted cells when allogenic MSC/bioscaffold combinations were grafted onto immunocompetent recipients without immunosuppressant therapy. This destruction blocked the recruitment process and did not allow the formation of new bone tissue. The possibility that the implanted exogenous MSCs could engage the host's osteoprogenitor cells to form new bone tissue could open new perspectives for the tissue engineering approach to bone repair, including the opportunity of using allogenic cells combined with a temporary immunosuppressant therapy, stimulating the replacement of the exogenous cells with autologous cells.

An automated enzyme metallographic silver in situhybridization method (SISH) has been reported to successfully determine human epidermal growth factor receptor 2 (HER2) gene amplification. We evaluated the staining and interpretative reproducibility of the HER2SISH assay at five laboratories and compared SISH results with other in situhybridization (ISH) methods. The HER2gene status of 89 breast carcinomas was analyzed in parallel using manual dual-color fluorescence ISH, manual chromogenic ISH, and bright-field automated SISH. A total of 1098 SISH-stained slides were evaluated. For comparison, all specimens were stained by 4B5 immunohistochemistry for HER2protein expression. Interpretation was performed by pathologists at five different laboratories using the algorithms provided by the manufacturers and the guidelines of American Society of Clinical Oncology/College of American Pathologists. Staining and interpretative reproducibility were measured through the computation of weighted kappa statistics. Following the optimization of SISH staining, 1077/1098 (98%) of slides were evaluable. Excellent reproducibility and efficacy of HER2SISH staining, and interobserver interpretation (Kw= 0.91), were observed among five sites. For the 89 invasive breast cancer cases, the overall rate of concordance between consensus 4B5 and consensus SISH, fluorescence ISH, and chromogenic ISH was 96.6% (86/89), 97.8% (87/89), and 96.6% (86/89), respectively. Overall concordance between positive and negative SISH and fluorescence ISH results, as well as between individual and consensus positive and negative SISH results, was excellent (P< 0.001).

Introduction: Although several molecular markers for bladder cancer have been identified, at present little information on prognostic biomarkers is available in the literature. Prognostication of this tumor is largely based on clinicopathological characteristics. Our aim was to identify nuclear matrix (NM) proteins that might serve to better characterize the phenotype of the invasive bladder cancer and to investigate their diagnostic and prognostic roles.Methods: NM proteins expressed in normal (n=3) or non-tumoral (n=9) tissue specimens and muscle-invasive bladder cancer (n=21) specimens were analyzed by two dimensional (2D) gel electrophoresis. PDQuest image analysis software was used to generate a comparative NM proteome analysis. Selected spots were characterized by liquid chromatography coupled to tandem mass spectrometry and Western blot.Results: We detected over 800 protein spots in each 2D map and 43 spots were identified. 30 proteins were differentially expressed by bladder tumor cells; among these, 19 proteins were detected in bladder tumoral tissues but not in normal and non-tumoral tissues and seven proteins correlated with tumor stage. One protein (p54nrb) was strongly correlated with vascular invasions and appeared to be also significantly (P<0.0001) associated with a decreased probability of survival.Conclusion: Important alterations in NM proteins occur in muscle-invasive bladder cancer. The differentially expressed proteins include biomarkers potentially useful for disease diagnosis, progression and prognosis. Our findings beyond improving the understanding of the biology of bladder cancer, could help to stratify patients into different prognostic subgroups and to select those who might be better candidate to multimodal therapeutic approaches.