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What will be the biggest issues/topics in research and treatment of glioblastoma in the next years?

Glioblastoma is a highly aggressive primary malignant tumor with a <4% 5-year survival rate. Standard treatment is surgery to remove as much of tumor as possible (surgical resection) followed by radiation and Temozolomide, a DNA methylating agent. Options are extremely limited for recurring tumors.This answer highlights immunotherapies for glioblastoma. Don't know about biggest but currently four major research approaches dominate glioblastoma immunotherapy and likely will do so in the near future.Heat shock protein vaccinesPeptide immunotherapyDendritic cell (DC) vaccinesOncolytic virusesHeat shock protein vaccinesBased on Pramod K. Srivastava's novel finding that heat shock proteins drive tumor-specific immune responses (1).Heat shock proteins function as chaperones to proteins, helping in their proper folding and secretion.Heat shock proteins are also immunogenic, capable of driving immune responses against their cargo.Among the proteins expressed by tumors are tumor-specific proteins. Thus, heat shock proteins purified from tumor cells would be associated with tumor-specific antigens.Most commonly used heat shock protein in glioblastoma vaccines is HSP 96, a 96-kilodalton protein.Most prolific in this field are Andrew T. Parsa, his colleagues and collaborators.A Phase I trial (2) with HSP-96 glioblastoma vaccine (HSPPC-96; Prophage) showed it drove anti-glioblastoma immunity in 11/12 patients. Tumor biopsies showed T and NK cell infiltration.A Phase II trial (3) with 41 patients bolstered Phase I results with similar findings.Another HSP, HSP47, could be another glioblastoma target for two reasons (4).Expressed at high levels in glioblastoma but not in normal tissue.Patients with anti-HSP47 cytotoxic T cell response had better overall and progression-free survival.Drawbacks of Heat shock protein vaccines (5)Surgery necessary. This is an individualized Rx approach. Need as much of the tumor as possible since each patient's tumor itself is the source of their vaccine, HSPPC-96.Surgery being necessary means that only a small subset of patients with recurrent glioblastoma are eligible.If surgery yields insufficient tumor tissue, may not be possible to generate enough vaccine from it.Need to wait at least 1 month post-surgery to start vaccine Rx, time it takes to manufacture patient-specific vaccine.Survival outcomes currently not better than with standard anti-glioblastoma Rx, namely, lomustine or bevacizumab.Personalized vaccine, i.e., expensive.This table summarizes Glioblastoma heat shock protein vaccines (6).Peptide immunotherapyMost prolific in this field are John H. Sampson, his colleagues and collaborators.Current approach capitalizes on the observation that >90% glioblastomas, and not normal brain tissue, express Cytomegalovirus phosphoprotein 65 (pp65) RNA (7, 8, 9, 10).In their latest study (11), they preconditioned glioblastoma patients with either autologous mature dendritic cells (DCs) or tetanus/diphtheria toxoid one day before vaccinating with autologous DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA.Improved survival in patients preconditioned with tetanus/diphtheria toxoid.Caveats of this study were two-foldUnclear why tetanus/diphtheria toxoid preconditioning was compared to unpulsed DCs.Paper was under review with Nature for >1 year. Typically such long reviews suggest considerable tweaks were necessary to make data publication-worthy, meaning that original study data were weak and that reviewers demanded further experiments and/or additional controls.Drawbacks of Peptide immunotherapyMajority of glioblastoma peptide vaccines are restricted to the MHC haplotype, HLA-A*02 (12, 13). Won't work with glioblastoma patients with other MHC haplotypes.There is need to identify glioblastoma peptides presented by other prevalent MHC haplotypes.If and when tumor recurs, need to use different Rx approach. For example, earlier approaches targeted EGFRvIII (Epidermal Growth Factor Receptor), highly expressed on glioblastoma, i.e., a quasi-tumor-specific antigen. After this immunotherapy, 82% of patients with recurrence lost EGFRvIII expression (14). Implies two thingsPeptide vaccine successfully targeted EGFRvIII+ tumor cells.Peptide vaccine drove selective expansion of EGFRvIII- tumor cells.Suggests this Rx has potential to drive expansion of tumor escapees.Personalized immunotherapy, i.e., expensive.Dendritic cell (DC) vaccinesIn contrast to glioblastoma cells, which are poor at inducing immunity (15), DCs are antigen presenting cells necessary for fully activating CD4 and CD8 T cells.DCs shown to be excellent in presenting glioblastoma-derived antigens to T cells, activating anti-glioblastoma cytotoxic T cells and inducing tumor cell death (16, 17).Similar to heat shock protein vaccines and peptide immunotherapy, this is also personalized medicine.Purify patient's DCs from circulating blood, culture them during which they are pulsed/loaded with tumor lysates or peptides and then re-injected back into the patient.DC vaccines are among the most prevalent glioblastoma investigational immunotherapies under development (18, 19).Years of fine-tuning later, a Phase I trial revealed what's critical for DC vaccines to drive strong anti-glioblastoma immunity, namely, tumor lysates. Compared patients (n=28) treated with autologous DCs pulsed with autologous tumor lysates to those pulsed with synthetic glioblastoma antigen peptides (n=6). The former drove stronger anti-tumor immunity (20). This would fit with immunological predictions since tumor lysates would contain additional potential targets of strong anti-glioblastoma immunity, namely as-yet unidentified antigens,, i.e., a polyvalent response unlike defined peptides.Another line of investigation with DC vaccines. What are the biomarkers that correspond to effective anti-glioblastoma immunity? Phospho-STAT (21)? CTLA-4 (22)?Common drawbacks to HSP, peptide and DC vaccinesNeed tumor MHC class I expression.30 to 60% of glioblastoma population observed to be MHC class I- (23), i.e., potential that much of tumor won't be targeted by such immunotherapy.Targeting a single antigen may lead to tumor escapees so multiple targets, even multiple approaches may be necessary (18).Oncolytic virusesAn oncolytic virus is capable of replicating (24, 25).Engineered to selectively target and replicate in tumor cells. How (26)?Strategic mutations or deletions in viral genome that enhance their capacity to replicate within tumor cells while inhibiting the same in normal cells.Engineer virus to express tumor-antigen specific receptor, taking advantage of tumor-specific antigens expressed on tumor cell surface.Engineer virus to express viral genes under the control of promoters that will only be functional within tumor cells.Cause tumor cell death, either directly or indirectly by making the virus-infected tumor cell a target of immune cell-mediated responses.Drawbacks of Oncolytic virusesOnce virus is delivered to tumor, usually by injecting directly into it, host immune response kicks in to rapidly inactivate it before it can trigger sufficient tumor cell death.In order for the virus to make the tumor an excellent target of the ensuing anti-virus immunity, it needs to spread uniformly throughout the tumor. However, tumor is not simply a homogeneous bag of cells. It has a complicated microenvironment consisting of areas of lower oxygen tension (hypoxia) and unique extracellular matrix, which act as barriers limiting spread of virus within tumor.Preclinical models used thus far have been poor in predicting what would happen in human. Why? They grafted human glioblastoma into mice that lacked CD4 T cells (immunodeficient). Since such models lack one of the most important arms of immune function, they couldn't recapitulate likely scenario in human patients.Which virus to use? Answer not so easy (27). Need to be validated in preclinical models first but several problems ensueSpecies-specific virus effects. Virus may not have same effect in human as it does in mouse.HSV, Adeno, Polio are attenuated (weak) in mice but potent in humans.OTOH, Sindbis, pseudorabies and Vesicular Stomatitis viruses are pathogenic in mice, and not known to infect humans. When such viruses move to clinical trials after being engineered for anti-glioblastoma activity in mice, they create novel safety concerns.HSV (Herpes Simplex virus) has progressed furthest as an anti-glioblastoma oncolytic virus Rx. The following figures (25, 26) summarize the what and how of anti-glioblastoma oncolytic HSV and other viruses.BibliographySrivastava, Pramod K. "Purification of heat shock protein–peptide complexes for use in vaccination against cancers and intracellular pathogens." Methods 12.2 (1997): 165-171.Crane, Courtney A., et al. "Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein." Clinical Cancer Research 19.1 (2013): 205-214. Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone ProteinBloch, Orin, et al. "Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial." Neuro-oncology 16.2 (2014): 274-279. a phase II, single-arm trialWu, Zhe Bao, et al. "CTL responses to HSP47 associated with the prolonged survival of patients with glioblastomas." Neurology 82.14 (2014): 1261-1265.Chamberlain, Marc C. "Is there a role for vaccine-based therapy in recurrent glioblastoma?." Neuro-oncology 16.5 (2014): 757. Page on oxfordjournals.orgSee, Alfred P., et al. "Heat shock protein-peptide complex in the treatment of glioblastoma." (2011): 721-731.Cobbs, Charles S., et al. "Human cytomegalovirus infection and expression in human malignant glioma." Cancer research 62.12 (2002): 3347-3350. Human Cytomegalovirus Infection and Expression in Human Malignant GliomaMitchell, Duane A., et al. "Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma." Neuro-oncology 10.1 (2008): 10-18. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastomaRanganathan, Padhma, et al. "Significant association of multiple human cytomegalovirus genomic loci with glioblastoma multiforme samples." Journal of virology 86.2 (2012): 854-864. Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme SamplesDziurzynski, Kristine, et al. "Consensus on the role of human cytomegalovirus in glioblastoma." Neuro-oncology 14.3 (2012): 246-255.Consensus on the role of human cytomegalovirus in glioblastomaMitchell, Duane A., et al. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (2015): 366-369. Page on nature.comPhuphanich, Surasak, et al. "Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma." Cancer Immunology, Immunotherapy 62.1 (2013): 125-135. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastomaNeidert, Marian Christoph, et al. "Natural HLA class I ligands from glioblastoma: extending the options for immunotherapy." Journal of neuro-oncology 111.3 (2013): 285-294.Sampson, John H., et al. "Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma." Journal of Clinical Oncology 28.31 (2010): 4722-4729. Immunologic Escape After Prolonged Progression-Free Survival With Epidermal Growth Factor Receptor Variant III Peptide Vaccination in Patients With Newly Diagnosed GlioblastomaIshikawa, Eiichi, et al. "Clinical trial of autologous formalin‐fixed tumor vaccine for glioblastoma multiforme patients." Cancer science 98.8 (2007): 1226-1233. Page on wiley.comCohn, Lillian, and Lélia Delamarre. "Dendritic cell-targeted vaccines." Frontiers in immunology 5 (2014). Dendritic Cell-Targeted VaccinesAnguille, Sébastien, et al. "Clinical use of dendritic cells for cancer therapy." The lancet oncology 15.7 (2014): e257-e267. Page on researchgate.netOh, Taemin, et al. "Vaccine therapies in malignant glioma." Current neurology and neuroscience reports 15.1 (2015): 1-7.Sayegh, Eli T., et al. "Vaccine therapies for patients with glioblastoma." Journal of neuro-oncology 119.3 (2014): 531-546.Prins, Robert M., et al. "Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients." Journal of immunotherapy (Hagerstown, Md.: 1997) 36.2 (2013): 152. Page on nih.govEverson, Richard G., et al. "Cytokine responsiveness of CD8 (+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients." J Immunother Cancer 2.10 (2014). Page on biomedcentral.comFong, Brendan, et al. "Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients." PloS one 7.4 (2012): e32614-e32614. Page on plosone.orgYamanaka, Ryuya. "Cell-and peptide-based immunotherapeutic approaches for glioma." Trends in molecular medicine 14.5 (2008): 228-235.Russell, Stephen J., Kah-Whye Peng, and John C. Bell. "Oncolytic virotherapy." Nature biotechnology 30.7 (2012): 658-670. Page on nih.govNing, Jianfang, and Hiroaki Wakimoto. "Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy." Frontiers in microbiology 5 (2014). Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapyDey, Mahua, et al. "Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making?." Future virology 8.7 (2013): 675-693. Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making?Wollmann, Guido, Koray Ozduman, and Anthony N. van den Pol. "Oncolytic Virus Therapy of Glioblastoma Multiforme–Concepts and Candidates." Cancer journal (Sudbury, Mass.) 18.1 (2012): 69. Oncolytic Virus Therapy of Glioblastoma Multiforme – Concepts and Candidates

What is the probability that extraterrestrial intelligence exists?

There are plethora of Scientific researches going on to discover extraterrestrial life .Astronomers have spotted some planets outside solar system where they found some signs of habitats. As per my information there have been quite astonishing evidences for the existence of life in our solar system.Yeah,you read it write .We don't need to go outside of our Solar System. I have prepared a list of celestial objects of our solar system .Along with chances of life ,there are some ifs and buts Indeed.Mars:Planet in our solar systemChances: There are signs that liquid water flows on the martian surface .Its atmosphere is thought to be thicker in the past. NASA has already sent its Curiosity Rover to the Mars.India's Mars orbiter Mission (MOM) is is doing good. On Mars there have been strong evidences of organic building blocks including Carbon,Hydrogen, Phosphorus and Nitrogen . These are the constituents of amino acids and DNA which are building blocks of LifeAmbiguity: There are some doubts.Zero traces of ancient life found ,samples needed for analysis.Water found in soil is mutually locked to minerals and inaccessibleNow ,Very thin atmosphere2. Venus:PlanetChances:Venus the sister of the Earth ,it is similar to the earth in size and distance from the sunVenus Contains chemicals in its lithosphere that could be caused by living thingsIt might have featured similar environment to earth,including oceans.Doubts:There has been no evidence of waterIts surface is smoking hot .It hovers around 864 FahrenheitIt possesses extreme atmospheric pressure approximately 90 times what it feels like at sea level on our earth3. Europa: Moon of JupiterChances:Water ice could exist between surface and underground liquid water layer .It has been strongly acclaimed by Sir Stephen Hawking.Even more tidal force on Jupiter may generate heat in underground oceansVolcanic eruptions could provide heat and chemical building blocks of lifeAmbiguities :There are so many unknowns about Europa, NASA is planning to send a spacecraft there in 2020s.4. Ganymede:Jupiter's MoonHopes:It has ocean underneath the icy crustGanymede has strong magnetic field which indicated presence of metals in its coreIt is probable to possess an atmosphere containing oxygen.Doubts: Unfortunately, we have a lot to learn. The European Space Agency (ESA) ‘s JUICE orbiter should reach it by the 2030s.5. Callisto:Jupiter's MoonChances: It has ocean underneath its icy surface.Doubt: The biggest doubt that comes to my mind is that “if there is a ocean,it is a cold one that reliefs on radioactivity for heat”.6. Lo:Moon of JupiterChances:It has sustainable thin atmosphereProfuse Volcanic activityOutside life chances evolved on surface when conditions were more favorable then retreated underground to avoid geothermal activityDoubts:It sits inside Jupiter's magnetic field.It gets pounded by lots of radioactive material.Some parts are incredible hot.No water found yet.7. Enceladus: Saturn's moonHopes:There have been signs of tidal forces and stressing by orbit with Saturn which could generate Heat,plumes of water shoot from cracks in surface ,suggesting an underground ocean underneath icy surface.Doubts- Biggest thing that comes my mind is it is intensely cold.8. Titan:Moon of SaturnHopes:It has thick atmosphereAtmospheric air contains methane, life on earth generates methane.Doubts:It is incredibly coldSurprisingly ,here water is present but its chemical texture doesn't sustain any life we know of.9- Ceres:Dwarf PlanetHopeful:It contains water vaporThere have been signs of a lot of water ice on its surfaceDoubtful:We have a lot to explore from NASA ‘s Dawn mission,which has been observing this dwarf planet since 2015.

Transgender: What is the physical/physiological/neurological evidence for transsexuality?

Yes. Decades worth, going all the way back to 1966. And much of it is available online with a quick google search. I'll do my best to give you a fairly robust sampling of the most important works at the end of this answer. The body of research on the veracity of trans patients' claims is not overwhelmingly large (by academic standards) but it is robust (by scientific standards), and it does hold up under peer-review and repeatability.However, if you're looking for some kind of litmus test to "prove" a living person's gender claim, you will not find it. The reason for this is that most of the research validating trans people's claims involves measuring the shape and size of specific portions of the brain, along with neuron counts and levels of specific neural transmitters. In each case study, research concludes that even in pre-hormonal and pre-surgical trans patients, portions of the archetecture of their brains fall measurably into the gendered category which they claim that they are. In other words, a trans woman's brain is empirically female under the microscope in specific, scientifically verifiable ways. Even in double-blind testing, scientists categorized trans patients into the gender that the patient said they were.You might have noticed the words "said" and "were". The catch is, these tests are mostly only possible post-mortem via dissection of the patient's brain and looking at it under a microscope. They are not generally tests one would perform on a living human. Some more recent efforts have been made using MRI scans to look at the brain's white matter, with some limited success. More research is needed to refine that process if it is to be useful as an indicator of feminized brains in male-designated patients, or vice versa.So for now, if a trans person informs you that she is a woman, you'll just have to take her word for it. She is the world's foremost expert on her own gender. And there is a very solid body of research which says that she's telling the truth.References:Bakker, Julie. "Sex Differentiation: Organizing Effects of Sex Hormones." Focus on Sexuality Research (2014) 3-23.Balen, Adam H., et al. “Polycystic ovaries are a common finding in untreated female to male transsexuals.” Clinical Endocrinology 38.3 (1993): 325-329.Bao, Ai-Min and Swaab, Dick F. “Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders” Frontiers in Neuroendocrinology 32 (2011): 214–226.Benjamin, H. (1966). The transsexual phenomenon. New York: Julian Press, page 85.Berglund, H. et al. “Male-to-Female Transsexuals Show Sex-Atypical Hypothalamus Activation When Smelling Odorous Steroids” Cerebral Cortex 18 (August, 2008): 1900—1908.*Cantor, James M. “New MRI Studies Support the Blanchard Typology of Male-to-Female Transsexualism” Arch Sex Behav40 (2011): 863–864.Coolidge, Frederick L., Linda L. Thede, and Susan E. Young. “The heritability of gender identity disorder in a child and adolescent twin sample.” Behavior Genetics 32.4 (2002): 251-257.Dessens, Arianne B., et al. “Prenatal exposure to anticonvulsants and psychosexual development.” Archives of Sexual Behavior 28.1 (1999): 31-44.Deori, Sean, et al. "Mapping Infant Brain Myelination with Magnetic Resonance Imaging." The Journal of Neuroscience 31.2 (2010): 784-791.Dorner, Gunter, et al. “Genetic and Epigenetic Effects on Sexual Brain Organization Mediated by Sex Hormones.” Neuroendocrinology Letters 22.6 (2001): 403-409.Emory, Lee E., et al. “Anatomic variation of the corpus callosum in persons with gender dysphoria.” Archives of Sexual Behavior 20.4 (1991): 409-417.Fontanari, Anna-Martha V. et al. “Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder” Journal of Psychiatric Research (2013): 1-3 (advance copy).Futterweit, Walter, Richard A. Weiss, and Richard M. Fagerstrom. “Endocrine evaluation of forty female-to-male transsexuals: Increased frequency of polycystic ovarian disease in female transsexualism.” Archives of Sexual Behavior 15.1 (1986): 69-78.Gooren, Louis “The biology of human psychosexual differentiation” Hormones and Behavior 50 (2006): 589–601.Green, Richard, and Eric B. Keverne. “The disparate maternal aunt–uncle ratio in male transsexuals: an explanation invoking genomic imprinting.” Journal of Theoretical Biology 202.1 (2000): 55-63.Green, Richard. “Family cooccurrence of “gender dysphoria”: Ten sibling or parent–child pairs.” Archives of Sexual Behavior 29.5 (2000): 499-507.Haraldsen, I. R. et al. “Sex-sensitive cognitive performance in untreated patients with early onset gender identity disorder”Psychoneuroendocrinology 28 (2003): 906–915.Hare, Lauren et al. “Androgen Receptor Repeat Length Polymorphism Associated with Male-to-Female Transsexualism” Biol Psychiatry 65.1 (January 1, 2009): 93–96.Hengstschläger, Markus, et al. “Sex chromosome aberrations and transsexualism.” Fertility and sterility 79.3 (2003): 639-640.Hines, Melissa, Charles Brook, and Gerard S. Conway. “Androgen and psychosexual development: Core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH).” Journal of Sex Research 41.1 (2004): 75-81.Hisasue, S. et al. "The relationship between second-to-fourth digit ratio and female gender identity." The Journal of Sexual Medicine (2012)Italiano, M. “Comment on Cantor” Arch Sex Behav 41 (2012):1079.Jolly, A. "The Wide Spectrum of Sex and Gender" Science 304.5673 (2004):965.Khandelwal, Ashish et al. “A 47,XXY Female with Gender Identity Disorder” Arch Sex Behav 39 (2010):1021–1023.Kruijver, Frank P. M. et al. “Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic Nucleus” The Journal of Clinical Endocrinology & Metabolism 85.5 (2000): 2034-2041.Ku, Hsiao-Lun et al. “Brain Signature Characterizing the Body-Brain-Mind Axis of Transsexuals” PLOS ONE 8.7 (July, 2013).Lamminmäki, Annamarja, et al. "Testosterone measured in infancy predicts subsequent sex-typed behavior in boys and in girls" Hormones and Behavior 61.4 (2012) 611-616Lentini, E. et al. “Sex Differences in the Human Brain and the Impact of Sex Chromosomes and Sex Hormones” Cerebral Cortex 23 (October, 2013): 2322-2336.Lombardo, Michael V. et al. "Fetal Testosterone Influences Sexually Dimorphic Gray Matter in the Human Brain" Journal of Neuroscience 32.2 (2012) 674-680Luders, Eileen et al. “Regional gray matter variation in male-to-female transsexualism” Neuroimage 46.4 (July 15, 2009): 904–907.Meyenburg, Bernd, and Volkmar Sigusch. “Kallmann’s Syndrome and Transsexualism.” Archives of Sexual Behavior 30.1 (2001): 75-81.Meyer-Bahlburg, Heino FL. “Transsexualism (“Gender Identity Disorder”)–A CNS-Limited Form of Intersexuality?.” Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology: Proceedings of the 2nd World Conference. Springer New York, 2011.Oh, Seok-Kyun et al. “Brain Activation in Response to Visually Evoked Sexual Arousal in Male-to-Female Transsexuals: 3.0 Tesla Functional Magnetic Resonance Imaging” Korean J Radiol 2012;13(3):257-264Rametti, Giuseppina et al. “White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study”Journal of Psychiatric Research 45 (2011): 199-204.Rametti, Giuseppina et al. “Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study” Psychoneuroendocrinology 37 (2012): 1261—1269.Sabalis, Robert F. et al. “The Three Sisters: Transsexual Male Siblings” Am J Psychiatry131 (August 8, 1974): 907-909.Sadeghi, Majid, and Ali Fakhrai. “Transsexualism in female monozygotic twins: A case report.” Australasian Psychiatry 34.5 (2000): 862-864.Savic, Ivanka and Arver, Stefan. “Sex Dimorphism of the Brain in Male-to-Female Transsexuals” Cerebral Cortex 21 (November, 2011): 2525—2533.Swaab, D.F. “Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation” Gynecol Endocrinol 19 (2004): 301–312.Winneke, G. et al. "Behavioral Sexual Dimorphism in School-Age Children and Early Developmental Exposure to Dioxins and PCBs: A Follow-Up Study of the Duisburg Cohort" Environmental Health Perspectives 10.1289 (2013) 1-32Yokota, Y. et al. “Callosal Shapes at the Midsagittal Plane: MRI Differences of Normal Males, Normal Females, and GID”Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference Shanghai, China, September 1-4, 2005.Zhou, Jiang-Ning, et al. “A Sex Difference in the Human Brain and its Relation to Transsexuality.” Nature 378.6552 (1995): 68-70.Zubiaurre-Elorza, Leire et al. “Cortical Thickness in Untreated Transsexuals”Cerebral Cortex Advance Access, published August 31, 2012.Zucker, Kenneth J., et al. “Psychosexual development of women with congenital adrenal hyperplasia.” Hormones and Behavior 30.4 (1996): 300-318.*The "Blanchard Typology" of Transsexualism is highly suspect and now largely discredited. The science on it is weak, and critics say it reduces gender identity to a matter of sexual attraction. Inclusion of this particular study on this list should not be taken as a tacit approval of that paradigm.

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