A synopsis of global frontiers in fertility preservation.

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of "Oncofertility Around the Globe" to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Are there sufficient numbers of low-risk basal cell carcinomas to justify general practitioners (family physicians) carrying out basal cell carcinoma surgery?

BACKGROUND: The incidence of basal cell carcinoma (BCC) is rising within the UK, and poses a significant workload on primary and secondary care services. Greater general practitioner (GP) involvement in the diagnosis and management of BCC has been suggested to reduce this burden. In 2010, the National Institute of Health and Care Excellence (NICE) produced guidelines on the management of low-risk BCCs by GP surgeons. AIM: To assess what proportion of BCCs are suitable for excision by GP surgeons, and to determine the potential demand for GP-led BCC surgery. METHODS: A retrospective analysis was undertaken of all BCCs excised over 32 months for a population of 795 000 from the West Midlands region, UK. The data collected were reviewed against NICE criteria to determine the number of BCCs suitable for excision by GP surgeons. RESULTS: In total, 1743 BCCs were excised over 32 months, a BCC excision rate of 82 per 100 000 population per year. Taking into account body site, diameter, histological subtype and other criteria, 3.0% (2.5 per 100,000 per year) of BCCs were considered low-risk according to the national criteria from NICE. CONCLUSION: Low-risk BCCs suitable for excision by GP surgeons are of low prevalence and it would be difficult for GPs to maintain competencies in BCC surgery. Dermatologists should continue to provide the lead in skin cancer diagnosis, treatment and management.

Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer's Disease Psychosis.

Psychosis in Alzheimer's disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer's disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Disseminated cutaneous Mycobacterium chelonae infection in an immunocompetent host.

Mycobacterium chelonae is a rare, rapidly growing, atypical acid-fast bacillus. Disseminated cutaneous infection has been reported in immunocompromised patients. We report an immunocompetent 86-year-old white woman, who presented with an 8-month history of extensive ulcerated abscess-like nodules. Mycobacterial culture confirmed M. chelonae infection and the patient was treated with a combination of clarithromycin and tobramycin. To our knowledge, this is the first reported case of spontaneous, disseminated cutaneous disease occurring in an immunocompetent patient.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Mechanism and stereoselectivity of asymmetric hydrogenation.

Rhodium complexes containing chiral phosphine ligands catalyze the hydrogenation of olefinic substrates such as alpha-aminoacrylic acid derivatives, producing chiral products with very high optical yields. Elucidation of the mechanisms of such reactions leads to the conclusion that the stereoselection is dictated not by the preferred initial binding of the substrate to the chiral catalyst, but rather by the much higher reactivity of the minor diastereomer of the catalyst-substrate adduct corresponding to the less favored binding mode.

Mechanisms of coenzyme B12-dependent rearrangements.

Coenzyme B12 serves as a cofactor in various enzymatic reactions in which a hydrogen atom is interchanged with a substituent on an adjacent carbon atom. Measurement of the dissociation energy of the coenzyme's cobalt-carbon bond and studies of the rearrangement of model free radicals related to those derived from methylmalonyl-coenzyme A suggest that these enzymatic reactions occur through homolytic dissociation of the coenzyme's cobalt-carbon bond, abstraction of a hydrogen atom from the substrate by the coenzyme-derived 5'-deoxyadenosyl radical, and rearrangement of the resulting substrate radical. The only role thus far identified for coenzyme B12 in these reactions--namely, that of a free radical precursor--reflects the weakness, and facile dissociation, of the cobalt-carbon bond.

A cytoplasmic inhibitor of the JNK signal transduction pathway.

The c-Jun amino-terminal kinase (JNK) is a member of the stress-activated group of mitogen-activated protein (MAP) kinases that are implicated in the control of cell growth. A murine cytoplasmic protein that binds specifically to JNK [the JNK interacting protein-1 (JIP-1)] was characterized and cloned. JIP-1 caused cytoplasmic retention of JNK and inhibition of JNK-regulated gene expression. In addition, JIP-1 suppressed the effects of the JNK signaling pathway on cellular proliferation, including transformation by the Bcr-Abl oncogene. This analysis identifies JIP-1 as a specific inhibitor of the JNK signal transduction pathway and establishes protein targeting as a mechanism that regulates signaling by stress-activated MAP kinases.

Observation of X-ray lines from a gamma-ray burst (GRB991216): evidence of moving ejecta from the progenitor.

We report on the discovery of two emission features observed in the x-ray spectrum of the afterglow of the gamma-ray burst (GRB) of 16 December 1999 by the Chandra X-ray Observatory. These features are identified with the Ly(alpha) line and the narrow recombination continuum by hydrogenic ions of iron at a redshift z = 1.00 +/- 0.02, providing an unambiguous measurement of the distance of a GRB. Line width and intensity imply that the progenitor of the GRB was a massive star system that ejected, before the GRB event, a quantity of iron approximately 0.01 of the mass of the sun at a velocity approximately 0.1 of the speed of light, probably by a supernova explosion.

Epithelioma cuniculatum: A case report.

Epithelioma cuniculatum (carcinoma cuniculatum) is a rare, low-grade verrucous carcinoma of the foot first described in 1954. We present a case report of a 55-year-old man with an enlarging lesion on the sole of his right foot. Despite initial benign pathology the lesion continued to grow, soften in consistency and develop a foul odour. Repeat biopsy showed a well-differentiated squamous cell carcinoma and below-the-knee amputation was required. Epithelioma cuniculatum presents as a slow growing mass on the plantar aspect of the foot. Diagnosis is often delayed and may require multiple biopsies. Lesions rarely metastasise but more commonly invade locally requiring wide surgical excision.

Ethnicity and other risk factors for acute lower limb cellulitis: a U.K.-based prospective case-control study.

BACKGROUND: Acute lower limb cellulitis is a common yet potentially serious condition. Previous studies have identified risk factors in the non-U.K. population. Ethnicity has been postulated as a possible risk factor but has not previously been investigated. OBJECTIVES: To identify risk factors for acute lower limb cellulitis in the U.K. population. METHODS: One hundred and fifty consecutive patients with cellulitis requiring hospital admission and 300 controls were recruited to this prospective case-control study. Controls were matched for age and sex. RESULTS: Strongly predictive risk factors for acute lower limb cellulitis in the U.K. include being of white ethnicity and preceding episodes of injury to the affected leg. No systemic illnesses were identified as increasing an individual's risk of presenting with cellulitis. CONCLUSIONS: This study has identified that patients of white ethnicity are at higher risk of developing acute lower limb cellulitis compared with other ethnic groups. The importance of local risk factors has also been shown in the U.K. population.

Trainee perspectives on postdoctoral recruitment in clinical neuropsychology: reflections on commentaries by Bodin and Grote (2016) and Nelson et al. (2016).

OBJECTIVE: The aim of the current invited paper is to provide the trainees' perspective on recent commentaries on recruitment for postdoctoral fellowship in clinical neuropsychology. The current system of recruitment includes both a match and non-match process and has been problematic for trainees and training programs alike. METHOD: The author team completed a non-systematic review of previously published commentaries on the current state of postdoctoral fellowship recruitment, which are briefly summarized in the current paper. The trainee perspective is addressed using both survey data and anecdotal experiences of the authors. RESULT: Trainees report high levels of dissatisfaction with the current dual recruitment system; however, there is no clear preference from trainees for either a match or non-match system. Trainees from both recruitment systems report high levels of satisfaction with their training experience. CONCLUSION: It seems that either a match or non-match approach, if it led to a unified system, would improve trainee satisfaction.

Pre-operative evaluation prior to soft tissue sarcoma excision - Why can't we get it right?

BACKGROUND: To define the association between an appropriate pre-operative workup (pre-operative advanced imaging studies, diagnostic biopsy) and incomplete soft tissue sarcoma (STS) excision. PATIENTS AND METHODS: This was a retrospective review of 397 consecutive patient records (2000-2008), looking at primary site advanced imaging (MRI or CT) and diagnostic biopsy procedures completed prior to the initial attempt at definitive surgical excision. Downstream effects of an inadequate pre-operative workup were also evaluated, including time to referral to a sarcoma multi-disciplinary care team and perceived alteration of surgical care in order to obtain a complete excision of the altered sarcoma bed. RESULTS: Thirty-eight percent (149/397) of soft tissue sarcomas identified underwent an incomplete excision prior to referral. A significant difference in the incidence of pre-operative primary site advanced imaging (91% vs. 42%, p < 0.001) and a pre-operative diagnostic biopsy (85% vs. 16%, p < 0.001) was found between the wide excision group and incomplete excision groups. Pre-operative biopsy (p < 0.001), tumor size >5 cm (p < 0.001), and a referral from an orthopaedic surgeon (p < 0.02) were all associated with reduced risk of incomplete excision in multivariate analysis. Seventy-four percent of patients in the incomplete excision group required an alteration in their definitive wide margin surgical resection, including rotational muscle flap coverage (37%), free flap coverage (11%), or amputation (11%). CONCLUSION: A minority of patients referred following incomplete excision of a STS had undergone an appropriate pre-operative workup prior to referral, leading to increased long-term morbidity following definitive re-excision. Education efforts to heighten awareness of suspicious soft tissue lesions remain vital.

Mechanism of lipid mobilization by the small intestine after transport blockade.

The nonionic detergent, Pluronic L-81 (L-81) has been shown to block the transport of intestinal mucosal triacylglycerol (TG) in chylomicrons. This results in large lipid masses within the enterocyte that are greater in diameter than chylomicrons. On removal of L-81, mucosal TG is rapidly mobilized and appears in the lymph. We questioned whether the blocked TG requires partial or complete hydrolysis before its transport. Rats were infused intraduodenally with [3H]glyceryl, [14C]oleoyl trioleate (TO) and 0.5 mg L-81/h for 8 h, followed by 120 mumol/h linoleate for 18 h. Mesenteric lymph was collected and analyzed for TG content and radioactivity. An HPLC method was developed to separate TG on the basis of its acyl group species. The assumed acyl group composition was confirmed by gas liquid chromatography analysis. TG lymphatic output was low for the first 8 h but increased to 52 mumol/h at the 11th h of infusion (3 h after stopping L-81). 38% of the infused TO was retained in the mucosa after the 8-h infusion. 95% of mucosal TG was TO, 92% of the radioactivity was in TG, and 2.4% of the 14C disintegrations per minute was in fatty acid. HPLC analysis of lymph at 6, 10, 12, and 14.5 h of infusion showed a progressive rise in TG composed of one linoleate and two oleates, to 39%; and in TG composed of two linoleates and one oleate to 20% at 14.5 h of infusion. On a mass basis, however, 80% of the TG acyl groups were oleate. 3H/14C ratios in the various TG acyl group species reflected the decrease in oleate. We conclude that first, unlike liver, most mucosal TG is not hydrolyzed before transport. The mechanism of how the large lipid masses present in mucosal cells after L-81 infusion are converted to the much smaller chylomicrons is unknown. Second, the concomitant infusion of linoleate did not impair lymph TG delivery after L-81 blockade.

Ethical, moral, and theological insights into advances in male pediatric and adolescent fertility preservation.

The successful treatment of boys with cancer has led to increasing attention to preserving their quality of life after completing cancer therapy. One of the top priorities for living a full life is keeping open the opportunity to have children. While sperm banking for males facing sterilizing cancer treatment can be effective, this approach requires subsequent use of reproductive procedures such as in vitro fertilization (IVF) or intrauterine insemination (IUI) to achieve a pregnancy. Advances in fertility preservation techniques may allow pre-pubertal boys to conceive using advanced stem cell technologies and stem cell transplantation in the future. This review summarizes the ethical positions of leading medical societies and explores the religious and moral stances of major religious institutions regarding these options.

Relationship between binding affinities to cellular retinoic acid-binding protein and in vivo and in vitro properties for 18 retinoids.

A new rapid assay has been developed for measurement of the binding of [3H]retinoic acid to cellular retinoic acid-binding protein. The assay, which uses activated charcoal for the separation of bound from unbound retinoic acid, was used to determine the concentration required to inhibit the binding of [3H]retinoic acid to cellular retinoic acid-binding protein by 50% for 18 retinoids with free carboxylic acid groups. Partially purified cellular retinoic acid-binding proteins isolated from rat testes and carcinogen-induced rat mammary tumors were used for these determinations. The following parameters were also determined for some or all of the retinoids: hypervitaminosis A doses; activity against carcinogen-induced mouse skin papillomas; inhibition of growth of a rat chondrosarcoma; inhibition of growth of 3T6 cells; and differentiation of the embryonal carcinoma cell line PCC4.azaIR. While all retinoids that are potent in these biological test systems bind tightly to cellular retinoic acid-binding protein, the converse is not true. The lack of a consistent quantitative correlation between 50% inhibitory concentration and biological activity is probably due to insufficient concentrations of the retinoid in the target tissue or celll, which is a consequence of factors such as absorbability, metabolism, tissue distribution, and pharmacokinetics.

Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia.

Using chronic myelogenous leukemia (CML) as a model, we tested the hypothesis that cytokine-independent growth of leukemia cells results from aberrant activation of cytokine signaling pathways. The STAT5 (signal transducer and activator of transcription) protein, which is activated transiently in normal myeloid cells by cytokines such as GM-CSF (granulocyte-macrophage colony stimulating factor), was constitutively activated in cell lines derived from CML patients, even in the absence of GM-CSF. STAT5 was also activated in primary mouse bone marrow cells acutely transformed by the CML-specific BCR-ABL oncogene, but not by the serine kinase oncogene v-MOS. Reconstitution experiments in non-hematopoietic cells show that STAT5 activation by BCR-ABL occurs independent of cytokines. Results using BCR-ABL mutants which specifically uncouple connections to known signal transduction pathways show that STAT5 activation is kinase dependent and correlates directly with ability to confer cytokine independent growth in hematopoietic cells. BCR-ABL also activates JAK kinases, which may provide a mechanism for STAT activation. These findings are consistent with a role for STAT5 in hematopoietic transformation by BCR-ABL.

Fractionation of mucopolysaccharides by countercurrent distribution in aqueous polymer two-phase systems.

A new procedure for the fractionation of mucopolysaccharides based upon differences in their partition behavior in aqueous polymer two-phase systems has been devised. Systems containing dextran, poly(ethylene glycol), trimethylamino-poly(ethylene glycol), potassium bromide and sodium phosphate buffer were employed. Countercurrent distributions were performed with a miniature countercurrent distribution device designed especially for use with aqueous polymer two-phase systems. An advantage over the widely used procedures involving precipitation of mucopolysaccharides as their quaternary ammonium detergent complexes is that the countercurrent distribution pattern of a particular mucopolysaccharide is not affected by the simultaneous presence of other mucopolysaccharides. Preliminary distributions of labelled mucopolysaccharides isolated from the cells and culture medium of monolayer cultures of rat tumor cells demonstrate that the procedure is particularly well suited for the fractionation of very minute quantities of mucopolysaccharides.