The role of anti-EGFR therapies in EGFR-TKI-resistant advanced non-small cell lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the current recommended option for the first-line treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). Resistance to first-generation TKIs led to the development of second- and third-generation TKIs with improved clinical outcomes. However, sequential administration of TKIs has led to the emergence of new EGFR resistance mutations and persistent tumor cell survival. This evidence highlights the potential role of EGFR in transducing growth signals in NSCLC tumor cells. Therefore, dual inhibition of EGFR using combinations of anti-EGFR monoclonal antibodies (mAbs) and EGFR-TKIs may offer a unique treatment strategy to suppress tumor cell growth. Several clinical studies have demonstrated the benefits of dual blockade of EGFR using anti-EGFR mAbs coupled with EGFR-TKIs in overcoming treatment resistance in patients with EGFR-mutated NSCLC. However, a single treatment option may not result in the same clinical benefits in all patients with acquired resistance. Biomarkers, including EGFR overexpression, EGFR gene copy number, EGFR and KRAS mutations, and circulating tumor DNA, have been associated with improved clinical efficacy with anti-EGFR mAbs in patients with NSCLC and acquired resistance. Further investigation of biomarkers may allow patient selection for those who could benefit from anti-EGFR mAbs in combination with EGFR-TKIs. This review summarizes findings of recent studies of anti-EGFR mAbs in combination with EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC, as well as clinical evidence for potential biomarkers towards personalized targeted medicine.

WIP1 is a novel specific target for growth hormone action.

DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and γH2AX. We showed earlier that GH suppresses DDR by suppressing pATM, resulting in DNA damage accumulation. Here, we show GH acting through GH receptor (GHR) inducing wild-type p53-inducible phosphatase 1 (WIP1), which dephosphorylated ATM and its effectors in normal human colon cells and three-dimensional human intestinal organoids. Mice bearing GH-secreting xenografts exhibited induced colon WIP1 with suppressed pATM and γH2AX. WIP1 was also induced in buffy coats derived from patients with elevated GH from somatotroph adenomas. In contrast, decreased colon WIP1 was observed in GHR-/- mice. WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage. We elucidated a novel GH signaling pathway activating Src/AMPK to trigger HIPK2 nuclear-cytoplasmic relocation and suppressing WIP1 ubiquitination. Concordantly, blocking either AMPK or Src abolished GH-induced WIP1. We identify WIP1 as a specific target for GH-mediated epithelial DNA damage accumulation.

Síndrome de cascanueces acompañando un caso de síndrome de Wilkie: a propósito de un caso / Nutcracker Syndrome Combined with Wilkie Syndrome: Case Report

Resumen Objetivo: describir la presentación clínica, el diagnóstico y el tratamiento quirúrgico de un paciente con síndrome de la arteria mesentérica superior o síndrome de Wilkie combinado con síndrome de cascanueces o síndrome de compresión de la vena renal izquierda, en un centro de alta complejidad de un país latinoamericano. Descripción del caso: paciente masculino de 25 años, procedente de Estados Unidos, quien consultó por un año de pérdida de peso y episodios de obstrucción intestinal de etiología desconocida tras múltiples estudios de imagen. Se le realizaron estudios endoscópicos sin hallazgos; en la sala de recuperación desarrolló dolor abdominal que requirió ingreso al servicio de urgencias. La enterotomografía mostró dilatación de asas de colon e intestino delgado, con disminución del ángulo aortomesentérico y la serie gastrointestinal con paso filiforme del medio de contraste. Se intentó el manejo conservador como terapia inicial, con intolerancia al soporte nutricional entérico. Finalmente, se optó por el tratamiento quirúrgico, con un proceso de recuperación tórpido inicialmente, pero al final con resolución de los síntomas y aumento de peso. Conclusión: el síndrome de Wilkie es una enfermedad rara y un desafío diagnóstico en pacientes con pérdida de peso y dolor abdominal. Describimos un caso de compresión de la arteria mesentérica superior en el que se logró el diagnóstico con múltiples estrategias diagnósticas y resolución completa luego del tratamiento quirúrgico. La disminución del ángulo aortomesentérico puede comprimir la arteria mesentérica superior, así como la vena renal izquierda, que en ese caso resultó en un síndrome combinado de Wilkie y de cascanueces.

Abstract Objective: to describe the clinical presentation, diagnosis, and surgical treatment of a patient with superior mesenteric artery syndrome or Wilkie syndrome combined with the nutcracker syndrome or left renal vein compression syndrome in a tertiary referral center in a Latin American country. Case description: a 25-year-old male patient from the United States who attended for a year of weight loss and intestinal obstruction episodes of unknown etiology after multiple imaging studies. Endoscopic studies were performed without findings. While in the recovery room, he developed abdominal pain requiring admission to the emergency service. The CT enterography showed dilation of the colon loops and small intestine with a decrease of the aortomesenteric (AOM) angle and the gastrointestinal series with the filiform passage of the contrast medium. Conservative management was attempted as initial therapy with intolerance to enteric nutritional support. Finally, we initially opted for surgical treatment, with a slow recovery process, but in the end, with a resolution of symptoms and weight gain. Conclusion: Wilkie syndrome is a rare disease and a diagnostic challenge in patients with weight loss and abdominal pain. We described a superior mesenteric artery compression case in which diagnosis was achieved with multiple diagnostic strategies and complete resolution after surgical treatment. The decreased aortomesenteric angle may compress the superior mesenteric artery and the left renal vein. In this case, it resulted in a combined Wilkie and nutcracker syndrome.

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-ß and PD-L1 Pathways.

Cervical cancer is one of the most common and lethal cancers among women worldwide. Treatment options are limited in patients with persistent, recurrent, or metastatic cervical cancer, with <20% of women living >5 years. Persistent human papillomavirus (HPV) infection has been implicated in almost all cases of cervical cancer. HPV infection not only causes normal cervical cells to transform into cancer cells, but also creates an immunosuppressive environment for cancer cells to evade the immune system. Recent clinical trials of drugs targeting the PD-(L)1 pathway have demonstrated improvement in overall survival in patients with cervical cancer, but only 20% to 30% of patients show overall survival benefit beyond 2 years, and resistance to these treatments remains common. Therefore, novel treatment strategies targeting HPV infection-associated factors are currently being evaluated in clinical trials. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-ßRII receptor (a TGF-ß "trap") fused to a human immunoglobulin G1 monoclonal antibody that blocks PD-L1. Early clinical trials of bintrafusp alfa have shown promising results in patients with advanced cervical cancer.

Direct On-Chip Differentiation of Intestinal Tubules from Induced Pluripotent Stem Cells.

Intestinal organoids have emerged as the new paradigm for modelling the healthy and diseased intestine with patient-relevant properties. In this study, we show directed differentiation of induced pluripotent stem cells towards intestinal-like phenotype within a microfluidic device. iPSCs are cultured against a gel in microfluidic chips of the OrganoPlate, in which they undergo stepwise differentiation. Cells form a tubular structure, lose their stem cell markers and start expressing mature intestinal markers, including markers for Paneth cells, enterocytes and neuroendocrine cells. Tubes develop barrier properties as confirmed by transepithelial electrical resistance (TEER). Lastly, we show that tubules respond to pro-inflammatory cytokine triggers. The whole procedure for differentiation lasts 14 days, making it an efficient process to make patient-specific organoid tubules. We anticipate the usage of the platform for disease modelling and drug candidate screening.

Monovalent manganese based anodes and co-solvent electrolyte for stable low-cost high-rate sodium-ion batteries.

The demand of sustainable power supply requires high-performance cost-effective energy storage technologies. Here we report a high-rate long-life low-cost sodium-ion battery full-cell system by innovating both the anode and the electrolyte. The redox couple of manganese(I/II) in Prussian blue analogs enables a high-rate and stable anode. Soft X-ray absorption spectroscopy and resonant inelastic X-ray scattering provide direct evidence suggesting the existence of monovalent manganese in the charged anode. There is a strong hybridization between cyano ligands and manganese-3d states, which benefits the electronic property for improving rate performance. Additionally, we employ an organic-aqueous cosolvent electrolyte to solve the long-standing solubility issue of Prussian blue analogs. A full-cell sodium-ion battery with low-cost Prussian blue analogs in both electrodes and co-solvent electrolyte retains 95% of its initial discharge capacity after 1000 cycles at 1C and 95% depth of discharge. The revealed manganese(I/II) redox couple inspires conceptual innovations of batteries based on atypical oxidation states.