Central role of α7 nicotinic receptor in differentiation of the stratified squamous epithelium

Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte α7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of α7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with α-bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking α7 nAChR channels. Elimination of the α7 signaling pathway blocked nicotine-induced influx of 45Ca2+ and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the α7 nAChR pathway favored cell cycle progression. In the epidermis of α7−/− mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of α7 was associated with up-regulated expression of the α3 containing nAChR channels that lack α5 subunit, and both homomeric α9- and heteromeric α9α10-made nAChRs. Thus, this study demonstrates that ACh signaling through α7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca2+ influx

A novel BRCA-1 mutation in Arab kindred from east Jerusalem with breast and ovarian cancer

BACKGROUND: The incidence of breast cancer (BC) in Arab women is lower compared to the incidence in the Jewish population in Israel; still, it is the most common malignancy among Arab women. There is a steep rise in breast cancer incidence in the Arab population in Israel over the last 10 years that can be attributed to life style changes. But, the younger age of BC onset in Arab women compared with that of the Jewish population is suggestive of a genetic component in BC occurrence in that population. METHODS: We studied the family history of 31 women of Palestinian Arab (PA) origin affected with breast (n = 28), ovarian (n = 3) cancer. We used denaturing high performance liquid chromatography (DHPLC) to screen for mutations of BRCA1/2 in 4 women with a personal and family history highly suggestive of genetic predisposition. RESULTS: A novel BRCA1 mutation, E1373X in exon 12, was found in a patient affected with ovarian cancer. Four of her family members, 3 BC patients and a healthy individual were consequently also found to carry this mutation. Of the other 27 patients, which were screened for this specific mutation none was found to carry it. CONCLUSION: We found a novel BRCA1 mutation in a family of PA origin with a history highly compatible with BRCA1 phenotype. This mutation was not found in additional 30 PA women affected with BC or OC. Therefore full BRCA1/2 screening should be offered to patients with characteristic family history. The significance of the novel BRCA1 mutation we identified should be studied in larger population. However, it is likely that the E1373X mutation is not a founder frequent mutation in the PA population

Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias

IL7R-activating mutations identified in B-ALL and T-ALL patient leukemic cells facilitate cytokine-independent growth

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program

The Two-Brains Hypothesis: Towards a guide for brain-brain and brain-machine interfaces

Great advances have been made in signaling information on brain activity in individuals, or passing between an individual and a computer or robot. These include recording of natural activity using implants under the scalp or by external means or the reverse feeding of such data into the brain. In one recent example, noninvasive transcranial magnetic stimulation (TMS) allowed feeding of digitalized information into the central nervous system (CNS). Thus, noninvasive electroencephalography (EEG) recordings of motor signals at the scalp, representing specific motor intention of hand moving in individual humans, were fed as repetitive transcranial magnetic stimulation (rTMS) at a maximum intensity of 2.0T through a circular magnetic coil placed flush on each of the heads of subjects present at a different location. The TMS was said to induce an electric current influencing axons of the motor cortex causing the intended hand movement: the first example of the transfer of motor intention and its expression, between the brains of two remote humans. However, to date the mechanisms involved, not least that relating to the participation of magnetic induction, remain unclear. In general, in animal biology, magnetic fields are usually the poor relation of neuronal current: generally "unseen" and if apparent, disregarded or just given a nod. Niels Bohr searched for a biological parallel to complementary phenomena of physics. Pertinently, the two-brains hypothesis (TBH) proposed recently that advanced animals, especially man, have two brains i.e., the animal CNS evolved as two fundamentally different though interdependent, complementary organs: one electro-ionic (tangible, known and accessible), and the other, electromagnetic (intangible and difficult to access)-a stable, structured and functional 3D compendium of variously induced interacting electro-magnetic (EM) fields. Research on the CNS in health and disease progresses including that on brain-brain, brain-computer and brain-robot engineering. As they grow even closer, these disciplines involve their own unique complexities, including direction by the laws of inductive physics. So the novel TBH hypothesis has wide fundamental implications, including those related to TMS. These require rethinking and renewed research engaging the fully complementary equivalence of mutual magnetic and electric field induction in the CNS and, within this context, a new mathematics of the brain to decipher higher cognitive operations not possible with current brain-brain and brain-machine interfaces. Bohr may now rest

Quantitative Ratio of Primer Pairs and Annealing Temperature Affecting PCR Products in Duplex Amplification

The quantity of PCR products that are simultaneously amplified from two different loci in a duplex amplification (DA) are significantly lower for one of the loci, as compared to identical PCR amplification in separate single-band amplifications (SBA). This difference in amplification probably occurs already after the second cycle of amplification. To further analyze this phenomenon, we tested different reaction conditions, including annealing times, a wide range of temperatures, various quantities of the template, several nucleotide concentrations, different amounts of TaqI DNA Polymerase, number of amplification cycles and various amounts of primers and primers ratio. Changing the ratio between the sets of primers in DA had the most significant effect on the relative levels of amplification of the loci with an optimal ratio of 4:1 in favor of the set of primers used to amplify the underrepresented fragment. The optimal annealing temperatures for the tested sets of primers were identical in SBA and different in DA. Possible reasons for this phenomenon are discussed

Extreme Short Stature and Severe Neurological Impairment in a 17-Year-Old Male With Untreated Combined Pituitary Hormone Deficiency Due to POU1F1 Mutation

International audienceBackground: POU1F1 is an essential transcription factor for the differentiation, proliferation and survival of somatotrophs, lactotrophs, and thyrotrophs. Mutations in the POU1F1 gene are characterized by growth hormone (GH), thyrotropin, and prolactin deficiencies, commonly presenting with growth retardation and central hypothyroidism. Since the first report in 1992, more than 25 mutations have been identified in POU1F1.Case Description: We describe a 17-year-old male who presented to our Pediatric Endocrinology clinic with extreme short stature (height 81.7 cm, −9.3 SD), cognitive impairment, deaf-mutism, and neurological disabilities. L-thyroxine supplemental therapy, which had been initiated at the age of 6 months but ceased due to non-compliance, was reintroduced at presentation. GH therapy was initiated at 19 years of age, resulting in 42 cm linear growth, to a final height of 124 cm. Sequencing of POU1F1 revealed a previously described homozygous insertion mutation—c.580_581insT, p (Thr194Ilefs*7)—in exon 4 causing a frameshift that introduces a stop codon 7 amino acids downstream, leading to a severely truncated protein lacking the homeodomain.Conclusion: This case report sheds light on the natural history of untreated patients with POU1F1 mutations and raises awareness for early diagnosis and adequate treatment of central congenital hypothyroidism and GH deficiency