Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer

There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinum-resistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m−2 on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40–74 years). Median number of prior therapies is three (range 1–8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer

Combination of insulin and metformin in the treatment of type 2 diabetes

WSTĘP. Celem pracy była ocena działania metabolicznego metforminy w porównaniu z placebo, u chorych na cukrzycę typu 2, leczonych według schematu intensywnej insulinoterapii. MATERIAŁ I METODY. Metformina poprawia kontrolę glikemii u osób ze źle wyrównaną cukrzycą typu 2. Dotychczas nie zbadano jej wpływu u chorych na cukrzycę typu 2, leczonych metodą intensywnej insulinoterapii. Grupa 390 chorych na cukrzycę typu 2, stosujących insulinę, uczestniczyła w randomizowanym, kontrolowanym, przeprowadzonym metodą podwójnie ślepej próby badaniu z zaplanowaną pośrednią analizą po 16 tygodniach leczenia. Uczestników badania wybrano z 3 przyszpitalnych przychodni i losowo przydzielono do grup, przyjmujących placebo lub metforminę w uzupełnieniu insulinoterapii. Podczas badania prowadzono intensywną kontrolę glikemii z natychmiastowym dostosowaniem dawki insuliny, zgodnie ze ścisłymi wytycznymi. Określano wskaźniki kontroli glikemii, zapotrzebowanie na insulinę, masę ciała, ciśnienie tętnicze, stężenie lipidów, incydenty hipoglikemii i inne działania niepożądane. WYNIKI. Sposród 390 osób 37 nie ukończyło badania (12 w grupie otrzymującej placebo i 25 w grupie leczonej metforminą). U osób, które ukończyły 16-tygodniowy okres leczenia zastosowanie metforminy w porównaniu z placebo powodowało poprawę kontroli glikemii (średnia glikemia podczas 16 tygodni 7,8 vs. 8,8 mmol/l, p = 0,006; średnie stężenie HbA1c 6,9 vs. 7,6%, p < 0,0001), zmniejszone zapotrzebowanie na insulinę (63,8 vs. 71,3 j.; p < 0,0001), mniejszy przyrost masy ciała (-0,4 vs. +1,2 kg; p < 0,01) i zmniejszenie stężenia cholesterolu frakcji LDL (-0,21 vs. -0,02 mmol/l; p < 0,01). Ryzyko wystąpienia hipoglikemii było podobne. WNIOSKI. U chorych na cukrzycę typu 2, leczonych intensywnie insuliną, skojarzenie insuliny z metforminą powoduje lepsze wyrównanie glikemii w porównaniu z monoterapią insuliną, a jednocześnie zmniejsza zapotrzebowanie na insulinę i ogranicza przyrost masy ciała.INTRODUCTION. To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin. MATERIAL AND METHODS. Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured. RESULTS. Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P < 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P < 0.0001); reduced weight gain (&#8211;0.4 vs. +1.2 kg, P < 0.01); and decreased plasma LDL cholesterol (&#8211;0.21 vs. &#8211;0.02 mmol/l, P < 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS. In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

A brain-computer interface with vibrotactile biofeedback for haptic information

<p>Abstract</p> <p>Background</p> <p>It has been suggested that Brain-Computer Interfaces (BCI) may one day be suitable for controlling a neuroprosthesis. For closed-loop operation of BCI, a tactile feedback channel that is compatible with neuroprosthetic applications is desired. Operation of an EEG-based BCI using only <it>vibrotactile feedback</it>, a commonly used method to convey haptic senses of contact and pressure, is demonstrated with a high level of accuracy.</p> <p>Methods</p> <p>A Mu-rhythm based BCI using a motor imagery paradigm was used to control the position of a virtual cursor. The cursor position was shown visually as well as transmitted haptically by modulating the intensity of a vibrotactile stimulus to the upper limb. A total of six subjects operated the BCI in a two-stage targeting task, receiving only vibrotactile biofeedback of performance. The location of the vibration was also systematically varied between the left and right arms to investigate location-dependent effects on performance.</p> <p>Results and Conclusion</p> <p>Subjects are able to control the BCI using only vibrotactile feedback with an average accuracy of 56% and as high as 72%. These accuracies are significantly higher than the 15% predicted by random chance if the subject had no voluntary control of their Mu-rhythm. The results of this study demonstrate that vibrotactile feedback is an effective biofeedback modality to operate a BCI using motor imagery. In addition, the study shows that placement of the vibrotactile stimulation on the biceps ipsilateral or contralateral to the motor imagery introduces a significant bias in the BCI accuracy. This bias is consistent with a drop in performance generated by stimulation of the contralateral limb. Users demonstrated the capability to overcome this bias with training.</p

The C-Terminus of Toxoplasma RON2 Provides the Crucial Link between AMA1 and the Host-Associated Invasion Complex

Host cell invasion by apicomplexan parasites requires formation of the moving junction (MJ), a ring-like apposition between the parasite and host plasma membranes that the parasite migrates through during entry. The Toxoplasma MJ is a secreted complex including TgAMA1, a transmembrane protein on the parasite surface, and a complex of rhoptry neck proteins (TgRON2/4/5/8) described as host cell-associated. How these proteins connect the parasite and host cell has not previously been described. Here we show that TgRON2 localizes to the MJ and that two short segments flanking a hydrophobic stretch near its C-terminus (D3 and D4) independently associate with the ectodomain of TgAMA1. Pre-incubation of parasites with D3 (fused to glutathione S-transferase) dramatically reduces invasion but does not prevent injection of rhoptry bulb proteins. Hence, the entire C-terminal region of TgRON2 forms the crucial bridge between TgAMA1 and the rest of the MJ complex but this association is not required for rhoptry protein injection

High prevalence of ACE DD genotype among north Indian end stage renal disease patients

BACKGROUND: The Renin-Angiotensin system (RAS) is a key regulator of both blood pressure and kidney functions and their interaction. In such a situation, genetic variability in the genes of different components of RAS is likely to contribute for its heterogeneous association in the renal disease patients. Angiotensin converting enzyme-1 (ACE-1) is an important component of RAS which determines the vasoactive peptide Angiotensin-II. METHODS: In the present study, we have investigated 127 ESRD patients and 150 normal healthy controls from north India to deduce the association between ACE gene polymorphism and ESRD. The inclusion criteria for patients included a constantly elevated serum creatinine level above normal range (ranging from 3.4 to 15.8) and further the patients were recommended for renal transplantation. A total of 150 normal healthy controls were also genotyped for ACE I/D polymorphism. The criterion of defining control sample as normal was totally based on the absence of any kidney disease determined from the serum creatinin level. Genotyping of ACE I/D were assayed by polymerase chain reaction (PCR) based DNA amplification using specific flanking primers Based on the method described elsewhere. RESULTS: The difference of DD and II genotypes was found highly significant among the two groups (p = 0.025; OR = 3.524; 95%CI = 1.54-8.07). The combined genotype DD v/s ID+II comparison validated that DD genotype is a high risk genotype for ESRD (p = 0.001; OR = 5.74; 95%CI limit = 3.4-8.5). However, no correlation was obtained for different biochemical parameters of lipid profile and renal function among DD and non DD genotype. Interestingly, ~87% of the DD ESRD patients were found hypertensive in comparison to the 65% patients of non DD genotype CONCLUSION: Based on these observations we conclude that ACE DD genotype implicate a strong possible role in the hypertensive state and in renal damage among north Indians. The study will help in predetermining the timing, type and doses of anti-hypertensive therapy for ESRD patients

The search for the ideal biocatalyst

While the use of enzymes as biocatalysts to assist in the industrial manufacture of fine chemicals and pharmaceuticals has enormous potential, application is frequently limited by evolution-led catalyst traits. The advent of designer biocatalysts, produced by informed selection and mutation through recombinant DNA technology, enables production of process-compatible enzymes. However, to fully realize the potential of designer enzymes in industrial applications, it will be necessary to tailor catalyst properties so that they are optimal not only for a given reaction but also in the context of the industrial process in which the enzyme is applied

Split T Cell Tolerance against a Self/Tumor Antigen: Spontaneous CD4+ but Not CD8+ T Cell Responses against p53 in Cancer Patients and Healthy Donors

Analyses of NY-ESO-1-specific spontaneous immune responses in cancer patients revealed that antibody and both CD4+ and CD8+ T cell responses were induced together in cancer patients. To explore whether such integrated immune responses are also spontaneously induced for other tumor antigens, we have evaluated antibody and T cell responses against self/tumor antigen p53 in ovarian cancer patients and healthy individuals. We found that 21% (64/298) of ovarian cancer patients but no healthy donors showed specific IgG responses against wild-type p53 protein. While none of 12 patients with high titer p53 antibody showed spontaneous p53-specific CD8+ T cell responses following a single in vitro sensitization, significant p53-specific IFN-γ producing CD4+ T cells were detected in 6 patients. Surprisingly, similar levels of p53-specific CD4+ T cells but not CD8+ T cells were also detected in 5/10 seronegative cancer patients and 9/12 healthy donors. Importantly, p53-specific CD4+ T cells in healthy donors originated from a CD45RA− antigen-experienced T cell population and recognized naturally processed wild-type p53 protein. These results raise the possibility that p53-specific CD4+ T cells reflect abnormalities in p53 occurring in normal individuals and that they may play a role in processes of immunosurveillance or immunoregulation of p53-related neoplastic events