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Oncogenic CARD11 77030; Phone: 713-792-2860; Fax: 713-794-5656; e-mail: nfowler@ mutations in human diffuse large B cell lymphoma buy 130 mg malegra dxt amex. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting References 1 cheap malegra dxt 130 mg with visa. Targeting pathological B cell receptor results in rapid cell death. Duhren-von Minden M, Ubelhart R, Schneider D, et al. CLL B-cell receptors can kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or recognize themselves: alternative epitopes and structural clues refractory mantle cell lymphoma (MCL): durable efficacy and 558 American Society of Hematology tolerability with longer follow-up [abstract]. The Bruton’s cytic leukemia B-cell activation and migration. The Bruton tyrosine kinase (ASH Annual Meeting Abstracts). The Bruton’s tyrosine survival and tissue homing in vitro and in vivo. B-cell antigen naive (TN) and relapsed or refractory (RR) chronic lympho- receptor signaling enhances chronic lymphocytic leukemia cell cytic leukemia (CLL) or small lymphocytic lymphoma (SLL) migration and survival: specific targeting with a novel spleen patients including patients with high-risk (HR) disease: new tyrosine kinase inhibitor, R406. The Bruton’s tyrosine kinase- , , in patients with relapsed/refractory CLL. ASCO kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential Meeting Abstracts. The SYK tyrosine kinase: diffuse large b-cell lymphoma (DLBCL): interim results of a a crucial player in diverse biological functions. Nat Rev multicenter, open-label, phase 2 study [abstract]. Phase Ib trial of Syk with fostamatinib disodium has significant clinical activity AVL-292, a covalent inhibitor of Bruton’s tyrosine kinase in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Molecular pathways: targeting phos- tolerated and displays profound activity in high-risk chronic phoinositide 3-kinase p110-delta in chronic lymphocytic leuke- lymphocytic leukemia (CLL) patients [abstract]. Combinations of the phosphatidylinositol 3-kinase catalytic subunit that associates phosphatidylinositol 3-kinase-delta (PI3K) inhibitor Gs- with p85 and is expressed predominantly in leukocytes. J Biol 1101 (CAL-101) with rituximab and/or bendamustine are toler- Chem. Receptor lymphoma: results from a phase I study [abstract]. Blood (ASH tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid Annual Meeting Abstracts). The phosphoino- are tolerable and highly active in patients with relapsed or sitide 3 -kinase delta inhibitor, CAL-101, inhibits B-cell recep- refractory chronic lymphocytic leukemia (CLL): results from a tor signaling and chemokine networks in chronic lymphocytic phase I study [abstract]. B-cell receptor a phase 1 study of CAL-101, An isoform-selective inhibitor of triggers drug sensitivity of primary CLL cells by controlling phosphatidylinositol 3-kinase P110, in patients with glucosylation of ceramides. Oncogenically active (ASH Annual Meeting Abstracts). Exploiting synthetic demonstrates clinical activity and pharmacodynamic effects in lethality for the therapy of ABC diffuse large B cell lymphoma. Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 with 35. Chemokines and chemokine receptors in chronic bendamustine (B)/rituximab (R) (BR) in patients (pts) with lymphocytic leukemia (CLL): from understanding the basics relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): towards therapeutic targeting. A phase I trial of the tic strategy for chronic lymphocytic leukemia by combining Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI- GS-1101, a PI3 kinase delta (PI3K) inhibitor and a novel 32765), in combination with rituximab (R) and bendamustine in highly selective spleen tyrosine kinase (Syk) inhibitor, GS- patients with relapsed/refractory non-Hodgkin’s lymphoma 9973 [abstract]. A phase I/II study of evaluating activity and tolerability of BTK inhibitor PCI-32765 the selective phosphatidylinositol 3-kinase-delta (PI3K) and ofatumumab in patients with chronic lymphocytic leukemia/ inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with small lymphocytic lymphoma (CLL/SLL) and related diseases. Younes A, Flinn I, Berdeja J, Friedberg J, Alberti S. Phase 1b plasma levels and the risk for disease progression in chronic study combining ibrutinib with rituximab, cyclophosphamide, lymphocytic leukemia. Paraffin-based 6-gene with CD20-positive B-cell non-Hodgkin lymphoma (NHL). Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation.

One of the most advanced of Key research areas include: the resulting programs is the Biomarker Consortium (BC) generic malegra dxt 130mg on line. Within these target areas generic malegra dxt 130mg online, ● Rare diseases and stratified therapies; projects are funded that will: Hematology 2013 313 ● Facilitate the development and qualification of biomarkers; Some institutions are establishing their own venture funds to advance in-house discoveries. Partners Health Care, the parent ● Qualify biomarkers for diagnosing disease and predicting clinical organization of the Brigham and Women’s and Massachusetts response; General Hospitals, has been an early innovator in this area. With 30 million dollars in funding and professional staffing provided by ● Translate results to aid regulatory decision-making; and Partners, the fund is able to identify worthy discoveries, conduct due diligence, and partner with outside investors to create companies. The BC has established a simple process for investigators to submit a project concept for approval and funding. Applications are Academic centers, intent on maximizing the value of their reviewed on a rolling basis. Outsourcing various aspects of The Academic Drug Discovery Consortium (www. Individuals can join for free and be linked to a of fully integrated Chinese corporations that provide a compre- wealth of useful information. By working with these companies, a near Therapy Acceleration Program of the Leukemia & Lymphoma virtual enterprise can advance a new drug concept to the point of Society (www. Upfront payments, milestone have a high tolerance for risk, are willing to fund big “swing for the payments, and long-term royalty revenues will be increasingly fences” ideas, and can make decisions quickly. Efforts that risk-reduce assets will It is still too early to assess the impact of the PPP strategy, but these enhance their interest to corporate partners and increase their efforts are accelerating transformation of the drug discovery pro- intrinsic worth and, importantly, happy buyers will be repeat cess. Collaboration among commercial and nonprofit entities has customers. PPPs can catalyze the evolution of this new ecosystem. Conclusions Risk and failure will continue to be the norm for drug discovery. Getting the facts right Learning from failure is not a skill that is easily acquired. In the As I have noted already, the constant of failure is central to the rising academic world, we shun failure and failed results are rarely cost of pharmaceutical R&D. Wasting time and money on a bad published (except in the form of an occasional retraction). A topic of increasing interest and concern is the the pharmaceutical industry, a “fast to fail” mindset is seen as an common experience of published results that cannot be reproduced. To Scientists at Bayer reported that the company’s in-house experimen- suggest that success can be built from failure may be an extreme tal data do not match literature claims in 65% of target-validation view; however, it is likely that the rate of progress will improve if projects. Similarly, Amgen scientists report that they could not the new norm becomes an open discussion of failure rather than reproduce key results in reports of high interest to their oncology keeping failed results a secret. They have direct research, it is clearly a constant concern that the academic commu- access to patients, the definitive experimental system in drug nity must acknowledge and work to resolve. This institutional licensing offices want to make multiple lucrative deals is both an opportunity and a responsibility. Drug discovery is increasingly of interest to academic scientists. As industry tries to address the productivity gap and reduce the Several strategies have been initiated to provide an additional layer inefficiencies of its internal research efforts, opportunities are being of validation for ideas coming from nonprofit institutions. Elizabeth created for meaningful collaboration with academic partners. Iorns has started the Reproducibility Initiative, a consortium that allows scientists to submit studies to an independent advisory board for possible reproduction. If a project is selected, the scientist Disclosures provides funding and an independent laboratory conducts the Conflict-of-interest disclosure: The author is employed by Dyax Inc. Available from http:// Burt Adelman, Division of Hematology, Brigham and Women’s www.

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Courtesy David van Ham rupture (we call this ovulation) when it is 2 cm generic 130 mg malegra dxt. Figure 3 Endometrium in the follicular phase of the Figure 1 Schematic view of the different phases in the cycle: you can clearly see the triple line cheap malegra dxt 130mg on line. Courtesy David female menstrual cycle van Ham 171 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Table 1 Common causes of subfertility In woman No ovulation PCOS Hyperprolactinemia Early menopause Hypophysis/hormone abnormalities Tubes are not patent Hydrosalpinx Adhesions Proximal tube blockage Endometriosis Figure 4 Endometrium in the luteal phase of the cycle: Cervical hostility you can clearly see that the endometrium does not have triple lines anymore and has become dense. Courtesy In man David van Ham Semen not good enough Azoospermia Oligospermia is no longer triple layered (Figure 4). When the ovum is not fertilized or when the embryo Unexplained is not implanted in the endometrium, the next period will start. For an example of an ultrasound in women with PCOS, see Figure 7. CAUSES OF SUBFERTILITY • Hyperprolactinemia: the pituitary gland in the brain produces too much prolactin (hormone Causes of subfertility could be in the woman, in the that stimulates lactation). Typically these women man, in both, or unexplained (Table 1). In women, will have milk from the breast and a very irregu- the following three problems are the most common lar cycle. Rare causes are large stress: you can ask the patient if she lost a lot of fibroids or Asherman’s syndrome (adhesions of the weight recently. A follicle which ruptures and is fertilized is critical Tubes are not patent for becoming pregnant. Most women (around 91– 97%) with a regular cycle (between 25 and 35 days) This happens often after sexually transmitted infec- will produce a follicle monthly and thus have a tions (STI; see Chapter 17) and often women have chance of becoming pregnant5. The chances for a history of symptoms of STI/pelvic inflammatory women with oligomenorrhea becoming pregnant disease (PID) and sometimes chronic abdominal are less. If you can make an ultrasound you • Polycystic ovary syndrome (PCOS): this is a disease often can see hydrosalpinges (see Figure 6). You in which many small follicles grow (you can see can test the patency of the tubes in several ways (see it on ultrasound, per definition >12 follicles of section on Investigations on subfertility). Women will have oligomenorrhea (cycle of more than During the growth and development of a dominant 35 days) and are often (but not always) obese. An example of this mucus becomes very clear and forms threads. This questionnaire can be seen in the Appendix at the only happens around ovulation. You can also develop your own change in mucus is so that the sperm cells can swim form. The important questions are: up via the cervical mucus inside the uterus. In some • Duration of fertility problem: the longer the women, cervical mucus does not change and stays duration of the subfertility, the less likely it is white and is full of leukocytes: the sperm cells can- that you could help this couple. For example, if not use the mucus to swim up towards the follicle. In older women not mean that if sperm is of lower quality that it is (this does not count for men) fertility becomes a completely impossible to make a woman pregnant. Do not waste time and your patients’ Production of sperm cells takes 3 months and is money tackling infertility problems in women negatively influenced by high temperatures as in over the age of 42 years. If you find a poor sperm sample, you should • Ever pregnant before? Unexplained subfertility N Intrauterine fetal death (IUFD). We diagnose unexplained infertility if all the tests N Abortion (spontaneous, induced or dilatation are normal: the woman is ovulating, the tubes are and curettage, D&C). Any history of infec- patent, the cervical mucus is good, the post-coital tion around that abortion?

Fortunately cheap 130 mg malegra dxt with mastercard, the variety of causes of vaginal The differential diagnosis of first-trimester bleeding in early pregnancy is limited purchase 130mg malegra dxt visa. However, vaginal bleeding is best sub-divided according to differentiating between ectopic pregnancy and anatomical location; therefore your main focus miscarriage, both common causes of bleeding in should be to locate the anatomical origin of the early pregnancy, can sometimes be challenging. Diagnostic problems can especially arise in low- resource settings. This chapter specifically helps you prioritize your diagnosis and treatment. It also Table 1 Differential diagnosis of first-trimester vaginal helps you identify the various causes of vaginal bleeding bleeding in the first trimester of pregnancy. Originating from uterus, tubes, amniotic sac with its Guidelines for proper history taking and physi- contents or placenta: cal examination will be given. After that, signs and • Ectopic pregnancy (see Chapter 12) symptoms and treatment options will be presented • Miscarriage (see Chapter 13) per cause. Finally, we will present a flow chart • Miscarriage with infection (see Chapter 13) which should guide you through the most impor- • Molar pregnancy (see Chapter 27) tant issues to be considered when encountering a • Subchorionic hemorrhage pregnant patient with vaginal bleeding in early • Idiopathic bleeding in a viable pregnancy pregnancy. The key points that are occasionally Originating from cervix or vagina: presented at the end of a section indicate the mini- • Infection (Chlamydia, etc. Life-threatening conditions are: 21 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Signs and symptoms of vaginal bleeding in the Box 1 Naegele’s rule first trimester An estimated EDD from the first day of the If a woman of reproductive age presents herself at woman’s LMP can be found by adding 1 year, your clinic with vaginal bleeding or any other subtracting 3 months and adding 7 days to that gynecological problem, always consider the possi- date. The result is approximately 280 days (40 bility that she might be pregnant. If she is aware of her pregnancy, she might have forgotten the date of her Example: last menstrual period. Only after assessing for a LMP = 8 May 2009 possible pregnancy can you start exploring the +1 year = 8 May 2010 patient’s complaint: vaginal bleeding. If pregnancy is likely, you length and it does not account for leap years. If you may confirm this by taking a urine pregnancy test want to be correct, you have to use a calendar. Exact (UPT) or, even better, an ultrasound if available at 280 days past LMP is found by checking the day of your facility. Only perform a UPT if you are in the week of the LMP and adjusting the calculated date doubt of possible pregnancy. This could save costs to land on the same day of the week. The calculated date (15 February) is a After confirmation of her pregnancy, try to assess Friday; adjusting to the closest Tuesday produces 12 the duration (or gestational age) of the pregnancy. This can be obtained by verifying the first day of her last menstrual period. With the LMP and Naegele’s rule one can estimate All these questions can give insight in the severity the expected date of delivery (EDD) and deduce of the case. A woman who suffered from bleeding the gestational age of the pregnancy (Box 1). If the which started before pregnancy might have cervical woman does not know the exact LMP, try to make or vaginal lacerations due to multiple reasons. A a reasonable estimate of the gestational age in woman with acute bleeding, who has to change weeks. Naegele’s rule assumes an average cycle her underwear frequently and suffers from accom- length of 28 days, which is not true for everyone. Nowadays Do not forget to check for other accompanying there are several online calculators as well, e. After assessing the gestational age of the patient’s • Provoked bleeding Is the bleeding spontaneous or pregnancy, you should explore her complaint. This could indi- Suggested questions for assessment of the vaginal cate a cervical origin of the problem, e. Did it start Do ask for other accompanying symptoms: acutely or gradually? Was it already present be- • Abdominal cramping pain: acute, continuous, fore pregnancy?

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