Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that about 40% of type 2 diabetes patients will develop nephropathy. In the past years, some research found that hypoxia response and hypoxia-inducible factors (HIFs) play critical roles in the pathogenesis of DN. Hypoxia-inducible factors (HIFs) HIF-1, HIF-2, and HIF-3 are the main mediators of metabolic responses to the state of hypoxia, which seems to be the one of the earliest events in the occurrence and progression of diabetic kidney disease (DKD). The abnormal activity of HIFs seems to be of crucial importance in the pathogenesis of diseases, including nephropathies. Studies using transcriptome analysis confirmed by metabolome analysis revealed that HIF stabilizers (HIF-prolyl hydroxylase inhibitors) are novel therapeutic agents used to treat anemia in CKD patients that not only increase endogenous erythropoietin production, but also could act by counteracting the metabolic alterations in incipient diabetic kidney disease and relieve oxidative stress in the renal tissue. In this review, we present the newest data regarding hypoxia response and HIF involvement in the pathogenesis of diabetic nephropathy and new therapeutic insights, starting from improving kidney oxygen homeostasis.

(1) Background: Because melanoma is an aggressive tumor with an unfavorable prognosis, we aimed to characterize the PD-L1 expression in melanomas in association with T cell infiltrates because PD-1/PD-L1 blockade represents the target in treating melanoma strategy. (2) Methods: The immunohistochemical manual quantitative methods of PD-L1, CD4, and CD8 TILs were performed in melanoma tumor microenvironment cells. (3) Results: Most of the PD-L1 positive, expressing tumors, have a moderate score of CD4+ TILs and CD8+TILs (5−50% of tumor area) in tumoral melanoma environment cells. The PD-L1 expression in TILs was correlated with different degrees of lymphocytic infiltration described by the Clark system (X² = 8.383, p = 0.020). PD-L1 expression was observed often in melanoma cases, with more than 2−4 mm of Breslow tumor thickness being the associated parameters (X² = 9.933, p = 0.014). (4) Conclusions: PD-L1 expression represents a predictive biomarker with very good accuracy for discriminating the presence or absence of malign tumoral melanoma cells. PD-L1 expression was an independent predictor of good prognosis in patients with melanomas.

Somatic mutations in the oncogenes of the epidermal growth factor receptor signaling pathway play vital roles in colorectal carcinogenesis and have been closely linked with clinical resistance to monoclonal therapy. In this study, we have analyzed the mutation frequencies of 5 genes and compared the genetic findings with clinicopathological variables in order to determine diagnostically relevant alterations and compare these findings with those of other studies In our Sanger sequencings, KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), BRAF (exon 15), AKT1 (exon 2) genes, and microsatellite instability (MSI) status were analyzed using an ABI 3500 analyzer in a cohort of 58 Romanian colorectal cancer (CRC) patients who underwent surgical resection at Emergency County Clinical Hospital in Constanța, Romania. In our series, mutation rates of KRAS, BRAF, PIK3CA, and AKT1 genes were 39.63%, 8.62%, 6.88%, and 3.44%, respectively. By contrast, we did not find any tumor harboring mutation in the NRAS gene. Notably, the KRAS and PIK3CA mutations were not mutually exclusive, 1 patient harbored 2 mutations in exon2, codon 12 (Gly12Val) of KRAS and exon 20, codon 1047 (His1047Arg) of PIK3CA. The finding of our study are generally consistent with data found in the literature. Regarding to clinicopathological variables, mutation of KRAS was associated with distant metastasis at the time of diagnosis, while mutation of BRAF was significantly associated with MSI-H in contrast with MSI-L/MSS tumors. Moreover, PIK3CA mutation tends to be located in the proximal segment of the colon and to be well/moderately differentiated compared to wild-type tumors. In conclusion, the assessment of these mutations suggests that CRC patients from southeast Romania exhibit a mutation profile similar to other populations. These results could contribute to creating a better method of qualifying patients for molecularly targeted therapies and obtaining better screening strategies.

This review brings together the current knowledge regarding the risk factors and the clinical, radiologic, and histological features of both post-COVID-19 pulmonary fibrosis (PCPF) and idiopathic pulmonary fibrosis (IPF), describing the similarities and the disparities between these two diseases, using numerous databases to identify relevant articles published in English through October 2022. This review would help clinicians, pathologists, and researchers make an accurate diagnosis, which can help identify the group of patients selected for anti-fibrotic therapies and future therapeutic perspectives.

Grade 4 adult gliomas are IDH-mutant astrocytomas and IDH-wildtype glioblastomas. They have a very high mortality rate, with survival at 5 years not exceeding 5%. We aimed to conduct a clinical imaging and morphogenetic characterization of them, as well as to identify the main negative prognostic factors that give them such aggressiveness. We conducted a ten-year retrospective study. We followed the clinical, imaging, and morphogenetic aspects of the cases. We analyzed immunohistochemical markers (IDH1, Ki-67, and nestin) and FISH tests based on the CDKN2A gene. The obtained results were analyzed using SPSS Statistics with the appropriate parameters. The clinical aspects representing negative prognostic factors were represented by patients’ comorbidities: hypertension (HR = 1.776) and diabetes mellitus/hyperglycemia (HR = 2.159). The lesions were mostly supratentorial, and the temporal lobe was the most affected. The mean volume was 88.05 cm³ and produced a midline shift with an average of 8.52 mm. Subtotal surgical resection was a negative prognostic factor (HR = 1.877). The proliferative index did not influence survival rate, whereas CDKN2A gene mutations were shown to have a major impact on survival. We identified the main negative prognostic factors that support the aggressiveness of grade 4 gliomas: patient comorbidities, type of surgical resection, degree of cell differentiation, and CDKN2A gene mutations.

Background and Aims: High-grade gastrointestinal neuroendocrine neoplasms (GI-NENs) are divided into well-differentiated G3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), having identical cut-offs of proliferation, but different biomolecular origins. This translates in distinct treatment choices. Our aim was to establish if p53/Rb1 immunohistochemical status in GI-NENs with Ki67 index >20% can predict the histopathological diagnosis. Methods: p53/Rb1 immunolabelling was performed on 42 cases of high-grade GI-NENs, diagnosed as NET G3, NEC and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) with NEC component. Immunolabeled slides were digitally scanned, with automatic quantification of p53 and Rb1, blind to the diagnosis. Results: The p53 positive percentage was stratified; two cut-offs were selected, naming the intervals as N (null, 20%). The Rb1 expression loss in >90% of neoplastic cells was considered mutational. NETs G3 mainly showed the T status (14/16, 87.5%), followed by N (1/16, 6.25%) and C (1/16, 6.25%); NECs and NEC components in MiNENs predominantly expressed the C status (19/26, 73.08%), followed by N (5/26, 19.23%) and T (2/26, 7.69%) (p<0.001, χ 2 =27.017). NET G3s showed positive expression for Rb1; 73.08% of NECs expressed negative Rb1 (p<0.001, χ 2 =21.351). NECs and NEC components in MiNENs showed Rb1 mutational status in 13 C cases (13/19, 68.42%), 4 N cases (4/5, 80%) and in both the T cases (p=0.002, χ 2 =11.187). Conclusions: Our results highlight the correlations between the p53/Rb1 immunostainings and the histopathological diagnosis of high-grade GI-NENs. NECs and NEC components in MiNENs showed a p53 mutational status (0% or 21-100%) and predominantly negative Rb1 expression. NETs G3 showed a p53 wild-type status (1-20%) and retained Rb1 expression. These findings suggest that the differential diagnosis of high-grade GI-NENs may benefit from p53/Rb1 immunohistochemical tests in everyday practice.