The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells.

Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs. p38 phosphorylation of RB increases its affinity toward the E2F transcription factor, represses gene expression, and delays cell-cycle progression. Remarkably, introduction of a RB phosphomimetic mutant in cancer cells reduces colony formation and decreases their proliferative and tumorigenic potential in mice.

Novel phases in ammonia-water mixtures under pressure.

While ammonia and water readily form hydrogen-bonded molecular mixtures at ambient conditions, their miscibility under pressure is not well understood, yet crucial to model the interior of icy planets. We report here on the behavior of ammonia-water mixtures under extreme pressure conditions, based on first-principles calculations of 15 stoichiometries in the pressure range of 1 atm-10 Mbar. We show that compression facilitates proton transfer from water to ammonia in all relevant mixtures. This favors ammonia-rich hydrates above 1 Mbar, stabilized by complete de-protonation of water and the formation of the unusual structural motifs O 2 - ⋅ ( N H 4 + ) 2 and O 2 - ⋅ ( N 2 H 7 + ) 2 . The hydronitrogen cations persist to the highest pressures studied. We predict a new ammonia-rich 4:1-hydrate at intermediate pressures and find that by 5.5 Mbar, close to the core-mantle boundary of Neptune, all cold ammonia-water mixtures are unstable against decomposition into their constituents.

PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors.

Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment.

A novel crystalline SiCO compound.

Ab initio evolutionary structural searches have been performed on SixCyO2(x+y) compounds. A novel structure, with SiC2O6 stoichiometry and the P21/c space group is calculated to be stable against decomposition within a wide pressure window from 7.2 to 41 GPa, and metastable under ambient conditions. It consists of CO3 units, linked to SiO6 octahedra, supporting previous experimental studies. The evolution of the carbon environment towards tetrahedral CO4 units, thus resembling the crystal chemistry of silicon, is predicted at higher pressures.

p85ß phosphoinositide 3-kinase subunit regulates tumor progression.

PIK3R2 encodes a ubiquitous regulatory subunit (p85ß) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85ß expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85ß expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik3r2 expression levels modulated tumor progression in vivo. Increased p85ß expression thus represents a cellular strategy in cancer progression.

From ELF to compressibility in solids.

Understanding the electronic nature of materials' compressibility has always been a major issue behind tabulation and rationalization of bulk moduli. This is especially because this understanding is one of the main approaches to the design and proposal of new materials with a desired (e.g., ultralow) compressibility. It is well recognized that the softest part of the solid will be the one responsible for its compression at the first place. In chemical terms, this means that the valence will suffer the main consequences of pressurization.It is desirable to understand this response to pressure in terms of the valence properties(charge, volume, etc.). One of the possible approaches is to consider models of electronic separability, such as the bond charge model (BCM), which provides insight into the cohesion of covalent crystals in analogy with the classical ionic model. However, this model relies on empirical parametrization of bond and lone pair properties. In this contribution, we have coupled electron localization function (ELF) ab initio data with the bond charge model developed by Parr in order to analyze solid state compressibility from first principles and moreover, to derive general trends and shed light upon superhard behavior.

High-pressure synthesis and characterization of iridium trihydride.

We have performed in situ synchrotron x-ray diffraction studies of the iridium-hydrogen system up to 125 GPa. At 55 GPa, a phase transition in the metal lattice from the fcc to a distorted simple cubic phase is observed. The new phase is characterized by a drastically increased volume per metal atom, indicating the formation of a metal hydride, and substantially decreased bulk modulus of 190 GPa (383 GPa for pure Ir). Ab initio calculations show that the hydrogen atoms occupy the face-centered positions in the metal matrix, making this the first known noninterstitial noble metal hydride and, with a stoichiometry of IrH(3), the one with the highest volumetric hydrogen content. Computations also reveal that several energetically competing phases exist, which can all be seen as having distorted simple cubic lattices. Slow kinetics during decomposition at pressures as low as 6 GPa suggest that this material is metastable at ambient pressure and low temperatures.

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors.

Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.

H2 Chemical Bond in a High-Pressure Crystalline Environment.

We show that the hydrogen in metal superhydride compounds can adopt two distinct states-atomic and molecular. At low pressures, the maximum number of atomic hydrogens is typically equal to the valency of the cation; additional hydrogens pair to form molecules with electronic states far below the Fermi energy causing low-symmetry structures with large unit cells. At high pressures, molecules become unstable, and all hydrogens become atomic. This study uses density functional theory, adopting BaH4 as a reference compound, which is compared with other stoichiometries and other cations. Increased temperature and zero-point motion also favor high-symmetry atomic states, and picosecond-timescale breaking and remaking of the bond permutations via intermediate H3- units.

Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities.

CONTEXT: Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour microenvironment (TME) in cancer biology with translational implications. Cancer-associated fibroblasts (CAFs) are a prominent, heterogeneous population of cells in the TME. CAFs have been associated with tumour development, progression, and poor prognosis in several neoplasms. However, their role in BLCA has not yet been exploited deeply. OBJECTIVE: To review the role of CAFs in BLCA biology and provide an understanding of CAF origin, subtypes, markers, and phenotypic and functional characteristics to improve patient management. EVIDENCE ACQUISITION: A PubMed search was performed to review manuscripts published using the terms "cancer associated fibroblast" and "bladder cancer" or "urothelial cancer". All abstracts were reviewed, and the full content of all relevant manuscripts was analysed. In addition, selected manuscripts on CAFs in other tumours were considered. EVIDENCE SYNTHESIS: CAFs have been studied less extensively in BLCA than in other tumours. Thanks to new techniques, such as single-cell RNA-seq and spatial transcriptomics, it is now possible to accurately map and molecularly define the phenotype of fibroblasts in normal bladder and BLCA. Bulk transcriptomic analyses have revealed the existence of subtypes among both non-muscle-invasive and muscle-invasive BLCA; these subtypes display distinct features regarding their CAF content. We provide a higher-resolution map of the phenotypic diversity of CAFs in these tumour subtypes. Preclinical studies and recent promising clinical trials leverage on this knowledge through the combined targeting of CAFs or their effectors and the immune microenvironment. CONCLUSIONS: Current knowledge of BLCA CAFs and the TME is being increasingly applied to improve BLCA therapy. There is a need to acquire a deeper understanding of CAF biology in BLCA. PATIENT SUMMARY: Tumour cells are surrounded by nontumoural cells that contribute to the determination of the behaviour of cancers. Among them are cancer-associated fibroblasts. The "neighbourhoods" established through these cellular interactions can now be studied with much greater resolution. Understanding these features of tumours will contribute to the designing of more effective therapies, especially in relationship to bladder cancer immunotherapy.

Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.

Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.

Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features.

Background and objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. Material and methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.

Screening Tools for Sarcopenia in Mild to Moderate Parkinson's Disease: Assessing the Accuracy of SARC-F and Calf Circumference.

BACKGROUND: Parkinson's disease (PD) and sarcopenia share similar pathophysiological mechanisms. OBJECTIVE: Estimate the prevalence of sarcopenia in PD patients and describe clinical and demographic features associated with sarcopenia. METHODS: A cross-sectional study was carried out at a tertiary public hospital in Brazil. A modified HY scale of stage 1 to 3, being at least 40 years old and having the ability to stand and walk unassisted were required for eligibility. We evaluated physical performance and muscle mass using DEXA. RESULTS: The study population comprised 124 patients, of which 53 (42.7%) were women. The mean age and mean disease duration were 65.8±10.5 and 10.1±5.8 years, respectively. The mean handgrip strength of 20.4±6.9 in woman and 34.6±8.4 kg in men. Moreover, 50.8% patients had positive SARC-F, 20% patients had probable sarcopenia, 9.6% confirmed sarcopenia, and 16.8% patients showed low muscle mass quantity measured by DEXA. Lower Levodopa Equivalent Dosage (LED) and calf circumference (CC) were independently associated with confirmed sarcopenia. LLED, higher MDS-UPDRS Part III, and lower MMSE scores were independently associated with probable sarcopenia. The CC demonstrated accuracy to identify PD patients with confirmed sarcopenia with a cut-off of <31 cm in women and <34 cm in men. CONCLUSION: We found low prevalence of confirmed sarcopenia among PD patients. We propose that healthcare providers introduce measuring CC, which is a quick and inexpensive method to assess for sarcopenia in PD patients.

Compression of silver sulfide: X-ray diffraction measurements and total-energy calculations.

Angle-dispersive X-ray diffraction measurements have been performed in acanthite, Ag(2)S, up to 18 GPa in order to investigate its high-pressure structural behavior. They have been complemented by ab initio electronic structure calculations. From our experimental data, we have determined that two different high-pressure phase transitions take place at 5 and 10.5 GPa. The first pressure-induced transition is from the initial anti-PbCl(2)-like monoclinic structure (space group P2(1)/n) to an orthorhombic Ag(2)Se-type structure (space group P2(1)2(1)2(1)). The compressibility of the lattice parameters and the equation of state of both phases have been determined. A second phase transition to a P2(1)/n phase has been found, which is a slight modification of the low-pressure structure (Co(2)Si-related structure). The initial monoclinic phase was fully recovered after decompression. Density functional and, in particular, GGA+U calculations present an overall good agreement with the experimental results in terms of the high-pressure sequence, cell parameters, and their evolution with pressure.

Specific function of phosphoinositide 3-kinase beta in the control of DNA replication.

Class I(A) phosphoinositide 3-kinase (PI3K) are enzymes comprised of a p85 regulatory and a p110 catalytic subunit that induce formation of 3-polyphosphoinositides, which activate numerous downstream targets. PI3K controls cell division. Of the 2 ubiquitous PI3K isoforms, alpha has selective action in cell growth and cell cycle entry, but no specific function in cell division has been described for beta. We report here a unique function for PI3Kbeta in the control of DNA replication. PI3Kbeta regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3Kbeta was found in the nucleus, where it associated PKB. Modulation of PI3Kbeta activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase delta. PI3Kbeta exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21(Cip). Also, p110beta associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3Kbeta in the control of DNA replication.

Chemically Assisted Precompression of Hydrogen Molecules in Alkaline-Earth Tetrahydrides.

Through a series of high pressure diamond anvil experiments, we report the synthesis of alkaline earth (Ca, Sr, Ba) tetrahydrides, and investigate their properties through Raman spectroscopy, X-ray diffraction, and density functional theory calculations. The tetrahydrides incorporate both atomic and quasi-molecular hydrogen, and we find that the frequency of the intramolecular stretching mode of the H2δ- units downshifts from Ca to Sr and to Ba upon compression. The experimental results indicate that the larger the host cation, the longer the H2δ- bond. Analysis of the electron localization function (ELF) demonstrates that the lengthening of the H-H bond is caused by the charge transfer from the metal to H2δ- and by the steric effect of the metal host on the H-H bond. This effect is most prominent for BaH4, where the precompression of H2δ- units at 50 GPa results in bond lengths comparable to that of pure H2 above 275 GPa.

Telehealth for Parkinson disease patients during the COVID-19 pandemic: the TeleParkinson study.

BACKGROUND: Telemedicine allows Parkinson disease (PD) patients to overcome physical barriers to access health care services and increases accessibility for people with mobility impairments. OBJECTIVE: To investigate the feasibility indicators of a telehealth intervention for PD patients, including patient recruitment, attendance, technical issues, satisfaction, and benefits on levels of physical activity and sleep. METHODS: We conducted a single-center, single-arm study of telehealth video consultations using WhatsApp (Meta Platforms, Inc., Menlo Park, CA, USA). Also, we collected the feasibility indicators as the primary endpoints. All the patients in the study were previously evaluated in person by the same team. RESULTS: Patient recruitment, attendance, and technical issues rates were 61.3%, 90.5%, and 13.3%, respectively, with good scores of patient acceptance and satisfaction with the study intervention. The telehealth intervention improved physical activity, including the number of walks for at least 10 continuous minutes (p = 0.009) and the number of moderate-intensity activities lasting at least 10 continuous minutes (p = 0.001). The Pittsburgh sleep quality index (PSQI) scores also improved for one of its components: perceived sleep duration (p < 0.001) and for total Pittsburgh score (p < 0,001). The average travel time saving was 289.6 minutes, and money-saving was R$106.67 (around USD 18; almost 10% of the current minimum wage in Brazil). CONCLUSIONS: Direct-to-patient telehealth video consultations proved to be feasible and effective and had a positive impact on physical activity levels and sleep in PD patients.

ANTECEDENTES: A telemedicina permite que pacientes com doença de Parkinson (DP) superem barreiras físicas para acessar serviços de saúde e aumenta a acessibilidade para pessoas com mobilidade reduzida. OBJETIVO: Investigar indicadores de viabilidade de uma intervenção em telessaúde para pacientes com DP, incluindo recrutamento, atendimento, aderência, problemas técnicos, satisfação e benefícios nos níveis de atividade física e sono. MéTODOS: Foi conduzido um estudo de centro e braço únicos baseado em consultas por telessaúde com utilização do WhatsApp (Meta Platforms, Inc., Menlo Park, CA, EUA). Foram calculados indicadores de viabilidade como desfechos primários. RESULTADOS: As taxas de recrutamento, atendimento e problemas técnicos foram 61,3%, 90,5% e 13,3%, respectivamente, com bons escores de aceitação e satisfação com a intervenção. A intervenção melhorou os níveis de atividade física, incluindo o número de passos por pelo menos 10 minutos contínuos (p = 0,009) e o número de atividades intensas e moderadas com duração de pelo menos 10 minutos contínuos (p = 0,001). O Índice de Qualidade do Sono de Pittsburgh melhorou nos seguintes componentes: duração percebida do sono (p < 0,001) e escore total (p < 0,001). A média do tempo de viagem médio poupado foi de 289,6 minutos, e a economia financeira foi de R$ 106,67 reais (por volta de USD 18; quase 10% do salário mínimo atual do Brasil). CONCLUSõES: As consultas por vídeo provaram ser viáveis e efetivas, com impacto positivo nos níveis de atividade física e sono de pacientes com DP.

Pressure-Induced Synthesis and Properties of an H2S-H2Se-H2 Molecular Alloy.

The chalcogens are known to react with one another to form interchalcogens, which exhibit a diverse range of bonding and conductive behavior due to the difference in electronegativity between the group members. Through a series of high-pressure diamond anvil experiments combined with density functional theory calculations, we report the synthesis of an S-Se hydride. At pressures above 4 GPa we observe the formation of a single solid composed of both H2Se and H2S molecular units. Further compression in a hydrogen medium leads to the formation of an alloyed compound (H2SxSe1-x)2H2, after which there is a sequence of pressure-induced phase transitions associated with the arrested rotation of molecules. At pressures above 50 GPa, there is a symmetrization of hydrogen bonds concomitantly with a closing band gap and increased reflectivity of the compound, indicative of a transition to a metallic state.

Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models.

BACKGROUND: The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. METHODS: We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. RESULTS: In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. CONCLUSIONS: Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.

Immunohistochemistry-Based Taxonomical Classification of Bladder Cancer Predicts Response to Neoadjuvant Chemotherapy.

BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). In retrospective studies, patients with basal/squamous (BASQ)-like tumors present with more advanced disease and have worse prognosis. Transcriptomics-defined tumor subtypes are associated with response to NAC. AIM: To investigate whether immunohistochemical (IHC) subtyping predicts NAC response. METHODS: Patients with muscle-invasive UBC having received platinum-based NAC were identified. Tissue microarrays were used to type tumors for KRT5/6, KRT14, GATA3, and FOXA1. OUTCOMES: progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. RESULTS: We found a very high concordance between mRNA and protein expression. Using IHC-based hierarchical clustering, we classified 126 tumors in three subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Applying multivariable analyses, patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017). The clinical benefit appeared reflected in the lack of significant survival differences between patients with BASQ-like and luminal tumors. CONCLUSIONS: Patients with BASQ-like tumors-identified through simple and robust IHC-have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation is required.