Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders.

There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis.

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of  (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of  that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the expressing neural crest.

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%).

Identification of novel mutations and phenotype in the steroid resistant nephrotic syndrome gene NUP93: a case report.

Background: Monogenic mutations may be a significant cause of steroid-resistant nephrotic syndrome. NUP93 is a gene previously reported to cause isolated steroid-resistant nephrotic syndrome.

Case Presentation: Here we describe a case of recessive, syndromic, steroid-resistant nephrotic syndrome caused by NUP93 mutation.

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models.

Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

Introduction: HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects.

Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma.

Background: The current tumor-node-metastasis system is inadequate to accurately classify patients in terms of prognosis. Thus, with the availability of recently developed molecular tools, considerable interest lies in discovering prognostic markers in order to guide treatment decisions. In this study, we sought to determine the prognostic significance of the cell cycle regulator cyclin D1 in oropharyngeal squamous cell carcinoma (OSCC).

Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets.

The perineuronal net forms the extracellular matrix of many neurons in the CNS, surrounding neuron cell bodies and proximal dendrites in a mesh-like structure with open "holes" at the sites of synaptic contacts. The perineuronal net is first detected late in development, approximately coincident with the transformation of the CNS from an environment conducive to neuronal growth and motility to one that is restrictive, suggesting a role for the perineuronal net in this developmental transition. Perineuronal nets show a great degree of molecular heterogeneity.