Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors: Part I--discovery of two binding modes

Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-alpha converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure-activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1'-S3' binding pockets, whereas mode B resides in the nonprime binding sites.     

Hair testing applied to the assessment of in utero exposure to drugs: Critical analysis of 51 cases of the University Hospital of Verona

The work discusses the results of hair and urine testing performed in 51 cases of suspected in utero drug exposure handled at the University Hospital of Verona from 2016 to 2022. On the day of birth or the day after birth, urine from mother and newborn (UM and UN) and hair from mother (HM), newborn (HN) and father (HF), if possible, were collected. Urine underwent immunoassay and GC–MS analysis, whereas hair underwent LC–MS/MS and GC–MS/MS analysis. In 50 out of 51 cases, HM and/or HN were available. In 92% of them, hair testing resulted in a positive, often (>50% cases) for more than one class of substance. The most detected substances were cocaine, opiates, methadone and cannabinoids. Maternal segmental analysis showed a prevalent decreasing concentration trend during pregnancy in case of positivity for one class of substances, whereas, as expected, a neatly prevalent increasing trend in the case of positivity for more than one class of substances. In nine cases, HF was also available, resulting in all being positive, usually for the same classes of substances identified in HM, thus questioning parental responsibility. In 33 cases, urine samples from the mother or newborn were also collected. Of them, 27 cases (82%) tested positive, showing peri-partum drug consumption and then confirming the severity of the addiction. Hair testing showed to be a reliable diagnostic tool to investigate in utero drug exposure because of the possibility of obtaining a complete picture of maternal addictive behaviour and family background, thanks to segmental maternal hair analysis and father hair testing.     

Thrombopoietin, interleukin-11, and early-acting megakaryocyte growth factors in human myeloid leukemia cells.

In this study we report our data on effects of early-acting megakaryocyte growth factors, particularly the c-mpl ligand also known as thrombopoietin (TPO) and interleukin-11 (IL-11), on cell proliferation and apoptosis (Apo) of primary acute myeloid leukemia (AML) cells. A proliferative response to TPO was noticed in the majority of AML samples (17/19) with an average increase of S-phase cells from 7.8% +/- 1.5 to 14.5% +/- 2.1 (p=0.0006). Resulting cell cycle activation did not always correlate with expression of the c-mpl receptor, although it was coupled, in the majority of samples, by an average decrease of apoptotic cells from 13% +/- 0.7 to 8.8% +/- 1.8 (p=0.05). Clonogenic cell growth (CFU-L) was confirmed in 5/17 of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. Conversely, effects of IL-11 on AML cells demonstrated that cell cycle changes (recruitment from G0 to S phase) were promoted only in a minority of samples (2/14) and there was little, if any, effect on CFU-L growth (mean colony number=17.5 +/- 9.5) or Apo (from 13% +/- 0.7 to 13.3 +/- 1.9). Combination of TPO with IL-11 induced a slight increase of clonogenic cell growth, while the addition of IL-3 or SCF to the c-mpl ligand significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 x 10(5) cells plated, respectively. In summary, TPO shows activity on AML cells by stimulating their proliferation in a significant proportion of cases and generally protecting the majority of AML blast cells from induction of Apo. Conversely, IL-11 exerts little effect on the cell cycle activation and Apo. These data help to understand regulation of myeloid leukemia cell growth and should be considered in the clinical use of early-acting megakaryocyte growth factors in acute leukemia.     

(68Ga)-PSMA-PET/CT for the detection of postoperative prostate cancer recurrence: Possible implications on treatment volumes for radiation therapy

PurposeThe aim of this study was to define the pattern of relapse of postoperative prostate cancer in patients by using 68Ga-labeled prostate-specific membrane antigen positron-emission tomography/computed tomography ([⁶⁸Ga]-PSMA PET/CT).Material and methodsForty patients received a (⁶⁸Ga)-PSMA PET/CT for biochemical failure. Following the Radiation Therapy Oncology Group (RTOG) guidelines, the pelvic clinical target volume has been contoured. Bone metastases were considered as outside the clinical target volume. Two subgroups of patients were defined, patients having relapse: (1) inside, or (2) outside the clinical target volume.ResultsGlobally, eight patients out of 32 presented with a positive lymph node failure inside the clinical target volume according to RTOG guidelines (25%), 22 patients had nodal relapses outside this clinical target volume (68.75%) and in two patients nodal relapses occurred both inside and outside of the clinical target volume (6.25%). Overall, 36 positive lymph node lesions were identified: of these, 23 nodal relapses were identified within the clinical target volume contoured according to RTOG and/or at the lomboaortic level (63%). To cover 95% of these 23 relapses, a hypothetical clinical target volume should encompass the nodal regions of the RTOG-defined clinical target volume as well as the paraaortic lymph node level up to T12-L1.ConclusionMost of the patients in the present study, presented with distant lymph node and/or bone metastases. Therefore, larger target volumes should be adopted to treat at least 95% of lymph node regions at risk for an occult relapse.     

18F-Fluorodeoxyglucose-PET/CT in locally advanced head and neck cancer can influence the stage migration and nodal radiation treatment volumes

Aim

To analyze the impact of 18F-fluorodeoxyglucose-PET/CT (PET/CT) in the radiotherapy (RT) planning strategy in HNC, correlating CT-scan and PET/CT performances.

Materials and methods

Inclusion criteria were: age >18 years old, histologically proven head and neck cancer (HNC), patients candidate to definitive RT ± chemotherapy, stage of disease by means of PET/TC and CT-scan performed at our Cancer Care Center.

Results

Sixty patients were analyzed. The following primary tumor sites were investigated: nasopharynx (13%), oropharynx (42%), oral cavity (32%) and larynx non-glottic (13%). Globally, PET/CT findings caused changes on nodal radiation treatment volumes in 10% of all the population of study. Specifically, in 5 cases out of 19 oral cavity tumors (26%), PET/CT detected neck-nodes positive (not detected at CT-scan). These findings have allowed to change the patients management, including PET/CT neck-nodes positive in the high-risk RT volumes.

Conclusion

In the RT planning strategy, the present findings support the use of PET/CT to improve upfront regional staging of HNC disease, particularly for oral cavity tumors. Further investigations are advocated to evaluate if this strategy could impact on long-term outcomes in terms of local control and overall survival.