Intrahost Selection Pressures Drive Rapid Dengue Virus Microevolution in Acute Human Infections.

Dengue, caused by four dengue virus serotypes (DENV-1 to DENV-4), is a highly prevalent mosquito-borne viral disease in humans. Yet, selection pressures driving DENV microevolution within human hosts (intrahost) remain unknown. We employed a whole-genome segmented amplification approach coupled with deep sequencing to profile DENV-3 intrahost diversity in peripheral blood mononuclear cell (PBMC) and plasma samples from 77 dengue patients. DENV-3 intrahost diversity appears to be driven by immune pressures as well as replicative success in PBMCs and potentially other replication sites. Hotspots for intrahost variation were detected in 59%-78% of patients in the viral Envelope and pre-Membrane/Membrane proteins, which together form the virion surface. Dominant variants at the hotspots arose via convergent microevolution, appear to be immune-escape variants, and were evolutionarily constrained at the macro level due to viral replication defects. Dengue is thus an example of an acute infection in which selection pressures within infected individuals drive rapid intrahost virus microevolution

The Ethical Implications of Intersex Surgery

Intersex individuals are born with sex characteristics that do not align with the binary expectations of male or female bodies. While intersex describes a wide variety of body phenotypes, some cases present visible intersex characteristics at birth, later on in life (puberty), or not at all. Intersex surgery uses medical intervention to modify atypical or ambiguous genitalia or sex characteristics. Individuals or their parents elect to undergo intersex surgery though it is not always medically necessary or advisable. The purpose of our study is to explore the biological and ethical underpinnings of intersex surgery over time

Screening of GPCR drugs for repurposing in breast cancer

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC

The abilities of improved schizophrenia patients to work and live independently in the community: a 10-year long-term outcome study from Mumbai, India

Background: The outcome of schizophrenia has several determinants. Socioecological factors, particularly living conditions, migration, community and culture, not only affect the level of risk but also the outcome. Mega cities around the world show a unique socioecological condition that has several challenges for mental health. The present study reports on the long-term status of patients with schizophrenia in such a mega city: Mumbai, India. Aim This study aims to reveal the long-term outcome of patients suffering from schizophrenia with special reference to clinical symptoms and social functioning. Methods: The cohort for this study was drawn from a 10-year follow-up of first episode schizophrenia. Patients having completed 10 years of consistent treatment after first hospitalisation were assessed on psychopathological and recovery criteria. Clinical as well as social parameters of recovery were evaluated. Descriptive statistics with 95% confidence intervals are provided. Results: Of 200 patients recruited at the beginning of this study, 122 patients (61%) were present in the city of Mumbai at the end of 10-year follow-up study period. Among 122 available patients, 101 patients (50.5%) were included in the assessment at the end of 10-year follow-up study period, 6 patients (3.0%) were excluded from the study due to changed diagnosis, and 15 patients (7.5%) were excluded due to admission into long-term care facilities. This indicates that 107 out of 122 available patients (87.7%) were living in the community with their families. Out of 101 (50.5%) patients assessed at the end of 10 years, 61 patients (30.5%) showed improved recovery on the Clinical Global Impression Scale, 40 patients (20%) revealed no improvement in the recovery, 43 patients (72.9%) were able to live independently, and 24 patients (40%) were able to find employment. Conclusions: With 10 years of treatment, the recovery rate among schizophrenia patients in Mumbai was 30.5%. Among the patients, 87.7% of patients lived in the community, 72.9% of patients lived independently, and 40% of patients obtained employment. However, 60% of patients were unable to return to work, which highlights the need for continued monitoring and support to prevent the deterioration of health in these patients. It is likely that socioecological factors have played a role in this outcome

The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.

BACKGROUND: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations. METHODS: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models. RESULTS: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance. CONCLUSIONS: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models

Intrahost Selection Pressures Drive Rapid Dengue Virus Microevolution in Acute Human Infections.

Dengue, caused by four dengue virus serotypes (DENV-1 to DENV-4), is a highly prevalent mosquito-borne viral disease in humans. Yet, selection pressures driving DENV microevolution within human hosts (intrahost) remain unknown. We employed a whole-genome segmented amplification approach coupled with deep sequencing to profile DENV-3 intrahost diversity in peripheral blood mononuclear cell (PBMC) and plasma samples from 77 dengue patients. DENV-3 intrahost diversity appears to be driven by immune pressures as well as replicative success in PBMCs and potentially other replication sites. Hotspots for intrahost variation were detected in 59%-78% of patients in the viral Envelope and pre-Membrane/Membrane proteins, which together form the virion surface. Dominant variants at the hotspots arose via convergent microevolution, appear to be immune-escape variants, and were evolutionarily constrained at the macro level due to viral replication defects. Dengue is thus an example of an acute infection in which selection pressures within infected individuals drive rapid intrahost virus microevolution