Members of the TGF-beta superfamily, which includes TGF-betas, growth differentiation factors, bone morphogenetic proteins, activins, inhibins, and glial cell line-derived neurotrophic factor, are synthesized as prepropeptide precursors and then processed and secreted as homodimers or heterodimers. Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions. Many studies have reported the characterization of knockout and knock-in transgenic mice as well as humans or other mammals with naturally occurring genetic mutations in superfamily members or their regulatory proteins. These investigations have revealed that TGF-beta superfamily ligands, receptors, SMADs, and upstream and downstream regulators function in diverse developmental and physiological pathways. This review attempts to collate and integrate the extensive body of in vivo mammalian studies produced over the last decade.

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Background Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).

In animals, including humans, the source of long-chain saturated fatty acids is de novo synthesis, which is mediated by fatty acid synthase (FAS), ingested food, or both. To understand the importance of de novo fatty acid synthesis, we generated FAS knockout mice. The heterozygous FAS mutants (Fasn ؉/؊ ) are ostensibly normal. In Fasn ؉/؊ mice the levels of FAS mRNA and the FAS activity are Ϸ50% and 35% lower, respectively, than those of WT mice; hence, FAS levels are affected by gene dosage. When the Fasn ؉/؊ mutant mice were interbred, Fasn ؊/؊ mice were not produced; thus, FAS is essential during embryonic development. Furthermore, the number of Fasn ؉/؊ progeny obtained was 70% less than predicted by Mendelian inheritance, indicating partial haploid insufficiency. Even when one of the parents was WT, the estimated loss of heterozygous progeny was 60%. This loss of Fasn ؉/؊ pups appeared to be strain-specific and became more pronounced as the heterozygous females produced more litters. Most of the Fasn ؊/؊ mutant embryos died before implantation and the Fasn ؉/؊ embryos died at various stages of their development. Feeding the breeders a diet rich in saturated fatty acids did not prevent the loss of homo-or heterozygotes. These observations are very important in considering teratogenic consequences of drugs aimed at inhibiting FAS activity, to reduce either obesity or the growth of cancerous tissues.F atty acid synthase (FAS; EC 2.3.1.85) of animal tissues is a homodimer and the monomer is a multifunctional protein containing seven catalytic domains and a site for the prosthetic group, 4Ј-phosphopantetheine. The FAS complex catalyzes the synthesis of the saturated fatty acids myristate, palmitate, and stearate by using the substrates acetyl-CoA, malonyl-CoA, and NADPH (1-4). FAS is highly expressed in tissues like liver, adipose, and lactating mammary glands (5). It is noteworthy that nearly every tissue in the human body has some level of FAS expression (5). FAS plays an important role in energy homeostasis by converting excess food intake into lipids for storage and providing energy when needed via ␤-oxidation. It is required for the generation of milk lipids during lactation. Besides being the apolar constituent of various membrane lipids required for membrane biogenesis and its functions, the products of FAS myristate (C14) and palmitate (C16) are involved in the myristoylation and palmitoylation of cellular and viral proteins for membrane targeting. The products of FAS, palmitate and stearate (C18), also serve as substrates for chain elongation to produce very-long-chain fatty acids. The latter fatty acids are important constituents of sphingolipids, ceramides, and glycolipids that are needed for cell division progression and brain structures and neurological functions (6). Further, increased FAS levels in cancer tissues indicate a poor prognosis (7-9). However, saturated fatty acids synthesized by FAS are readily available from food sources. Hence, the importance and contribution of the de novo fatty aci...

Smad5, together with Smad1 and Smad8, have been implicated as downstream signal mediators for several bone morphogenetic proteins (BMPs). Recent studies have shown that primordial germ cells (PGCs) are absent or greatly reduced in Bmp4 or Bmp8b mutant mice. To define the role of Smad5 in PGC development, we examined PGC number in Smad5 mutant mice by Oct4 whole-mount in situ hybridization and alkaline phosphatase staining. We found ectopic PGC-like cells in the amnion of some Smad5 mutant mice, however, the total number of PGCs was greatly reduced or completely absent in Smad5 mutant embryos, similar to Bmp4 or Bmp8b mutant embryos. Therefore, Smad5 is an important factor involved in PGC generation and localization.