A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk nonmuscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/ PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (p = 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (p = 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a preexisting Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.     

Form and magnitude of beta-sympathetic and parasympathetic influences on pulse transit time

In this study, we examined autonomic influences on pulse transit time measured from the R-wave of the electrocardiogram (R-PTT). Six subjects received three doses each of isoproterenol and atropine. Isoproterenol produced a significant linear decrease in R-PTT, a significant linear increase in heart rate (HR), and a significant linear decrease in diastolic blood pressure (DBP). Atropine produced a significant linear decrease in R-PTT and significant linear increases in HR and DBP. The R-PTT shortening effect of isoproterenol may reflect positive inotropic effects of beta- sympathetic myocardial stimulation. The R-PTT shortening effect of atropine may reflect reduction of parasympathetic inhibition of ventricular myocardial activity. However, possible vascular contributions to these effects remain to be determined. Nonetheless, the results encourage further examination of R-PTT in research concerning autonomic regulation of cardiovascular activity.     

The structural role of high molecular weight tropomyosins in dipteran indirect flight muscle and the effect of phosphorylation

In Drosophila melanogaster two high molecular weight tropomyosin isoforms, historically named heavy troponins (TnH-33 and TnH-34), are encoded by the Tm1 tropomyosin gene. They are specifically expressed in the indirect flight muscles (IFM). Their N-termini are conventional and complete tropomyosin sequences, but their C-termini consist of different IFM-specific domains that are rich in proline, alanine, glycine and glutamate. The evidence indicates that in Diptera these IFM-specific isoforms are conserved and are not troponins, but heavy tropomyosins (TmH). We report here that they are post-translationally modified by several phosphorylations in their C-termini in mature flies, but not in recently emerged flies that are incapable of flight. From stoichiometric measurements of thin filament proteins and interactions of the TmH isoforms with the standard Drosophila IFM tropomyosin isoform (protein 129), we propose that the TmH N-termini are integrated into the thin filament structural unit as tropomyosin dimers. The phosphorylated C-termini remain unlocated and may be important in IFM stretch-activation. Comparison of the Tm1 and Tm2 gene sequences shows a complete conservation of gene organisation in other Drosophilidae, such as Drosophila pseudoobscura, while in Anopheles gambiae only one exon encodes a single C-terminal domain, though overall gene organization is maintained. Interestingly, in Apis mellifera (hymenopteran), while most of the Tm1 and Tm2 gene features are conserved, the gene lacks any C-terminal exons. Instead these sequences are found at the 3’ end of the troponin I gene. In this insect order, as in Lethocerus (hemipteran), the original designation of troponin H (TnH) should be retained. We discuss whether the insertion of the IFM-specific pro-ala-gly-glu-rich domain into the tropomyosin or troponin I genes in different insect orders may be related to proposals that the IFM stretch activation mechanism has evolved independently several times in higher insects.     

Clinical efficacy in bleeding and surgery in von Willebrand patients treated with Fanhdi® a highly purified,doubly inactivated FVIII/VWF concentrate

Summary. Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi^®) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi^®. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi^® was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi^® a highly purified, doubly virus‐inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.     

Ankyloblepharon Filiforme Adnatum: Presentation of a Case

Abstract: Ankyloblepharon filiforme adnatum is a rare malformation, which may appear either in isolation, or with associated findings. We report a case of ankyloblepharon filiforme adnatum without associated anomalies, and discuss the management, and need for careful examination to exclude other anomalies.     

A STUDY OF DIETARY CALCIUM AND OTHER NUTRIENTS IN IDIOPATHIC RENAL CALCIUM STONE FORMERS WITH LOW BONE MINERAL CONTENT

Purpose

Patients with calcium renal stone are reported to have lower bone mineral density. The state of bone density in patients with renal stones have different explanations but the role of nutritional factors seems to be crucial. A group of 48 consecutive male calcium renal stone formers was studied to investigate the relationship between bone density and dietary intake.

Materials and Methods

Patients completed a dietary diary for a 3-day period during normal diet. Nutrients and calories were calculated by food composition tables using a computerized procedure. Bone densitometry was assessed at the lumbar spine and femoral neck, and expressed as Z score. A blood sample was collected and was analyzed for serum biochemistry including alkaline phosphatase, parathyroid hormone and 1,25 vitamin D. A 24-hour urine sample was analyzed for calcium, phosphate oxalate, citrate and other electrolytes.

Results

Dietary calcium intake was significantly lower (p <0.01) in patients with low than in those with normal bone mineral density. There was no difference in serum parathyroid hormone levels, phosphate and alkaline phosphatase between the 2 groups. The results suggest that some renal stone formers seem to be unable to decrease renal excretion of calcium on a low calcium diet leading to a negative calcium balance.

Conclusions

A primary abnormality of bone metabolism could be a reasonable explanation of reduced bone density observed in renal stone formers on a low calcium diet since serum parathyroid hormone levels are in the normal range. From a therapeutic point of view these data confirm that restriction of dairy products in renal stone formers should be avoided.     

METABOLIC BONE DISEASE INDUCED BY PROSTATE CANCER: RATIONALE FOR THE USE OF BISPHOSPHONATES

PURPOSE: Increasing evidences indicate that despite the osteoblastic nature of metastatic bone lesions due to prostate cancer osteolysis is a regular feature and may cause skeletal morbidity. This observation provides the rationale for the use of bisphosphonates for managing bone metastatic prostate cancer. MATERIALS AND METHODS: We reviewed the literature on the mechanisms by which prostate cancer affects bone cell function and disrupts physiological bone turnover. We also summarized the clinical results of bisphosphonate for treating bone pain in patients with prostate cancer. RESULTS: Metastatic prostate cancer in bone interferes with physiological bone remodeling by abnormal release of the hormones and paracrine factors physiologically involved in the modulation of osteoblastic and osteoclastic activity. Tumor induced bone formation and resorption develop within the same metastasis but excessive new bone is deposited away from bone resorption sites and does not contribute to bone strength. The increase in bone resorption may also be a generalized phenomenon that is most likely due to iatrogenic osteoporosis or related to hyperparathyroidism in response to the increased calcium demand. The bone resorption index in patients with bone metastatic prostate cancer correlates with bone pain and is an independent predictor of adverse skeletal events. However, small clinical studies of the efficacy of bisphosphonates for controlling bone pain in patients with prostate cancer show contradictory results. CONCLUSIONS: Improved understanding of the pathophysiology of prostate cancer induced metabolic bone disease implies that bisphosphonates may have a role in the treatment of this disorder. This issue is being addressed by large-scale ongoing randomized studies.     

Fc-binding molecules specific for human IgG1 and IgG3 are present in Echinococcus granulosus protoscoleces

In this work we describe the presence of Fc-binding activity on the suckers and tegument of E. granulosus protoscoleces. A fraction (PSA-Fc⁺) from protoscolex somatic antigens was isolated by affinity chromatography on human Fc-γ1-Sepharose. Analysis by SDS-PAGE of PSA-Fc⁺ showed that it contained two major components. Using mouse F(ab′)2-human Fc chimaeric monoclonal antibodies we verified that PSA-Fc⁺ bound mainly to human Fc-γ1 and Fc-γ3 isotypes. In addition, one of the components of PSA-Fc⁺ showed proteolytic activity. Both, Fc-binding and proteolytic activities localized on the protoscolex surface, may play a relevant role in the host-parasite interaction.