Objective:To assess the impact of preoperative short-course radiotherapy combined with neoadjuvant chemotherapy on elderly patients with locally advanced rectal cancer after a 2-year follow-up.Methods:In this retrospective cohort study, we included 446 consecutive cases of elderly patients diagnosed and treated for locally advanced rectal cancer(stage Ⅱ-Ⅲ with T3-T4 and/or positive regional lymph nodes)at the First People's Hospital of Shangqiu city from January 2012 to December 2019.The patients were divided into two groups based on the treatment method: an observation group(107 cases)and a control group(339 cases).The patients in the observation group underwent preoperative short-course radiotherapy combined with neoadjuvant chemotherapy.The regimen included short-term radiotherapy(25 Gy over 1 week in 5 fractions)followed by 4 courses of chemotherapy(CAPOX regimen).On the other hand, the control group received concurrent radiotherapy and chemotherapy.The regimen involved 50 Gy over 5 weeks in 25 fractions and concurrent capecitabine chemotherapy.Afterward, total rectal mesentery resection was performed, and postoperatively, 2 and 6 courses of CAPOX chemotherapy were continued.Follow-up was conducted until 31 December 2021, with the primary observation being the disease-free survival(DFS)of patients in both groups.Secondary observations included overall survival(OS)time, lesion progression-free survival(PFS)time, local recurrence rate, and the rate of acute toxicity events.Cox regression analyses were conducted to compare the factors influencing DFS.Results:Among the 446 patients, 303(67.9%)were male and 143(32.1%)were female.The patients in the observation group were found to be younger and had a higher proportion of Eastern Collaborative Oncology Group(ECOG)physical status score 0 compared to the control group(both P<0.05).Additionally, the two groups differed significantly in terms of MRI T stage, N stage, distance from the external anal verge, rectal mesorectal fascial infiltration, pathological stage, and chemotherapy-to-surgery time interval(all P<0.05).Throughout a mean follow-up period of(20.7±3.5)months, there were 76 deaths, 89 distant metastases, and 32 local recurrences.The results of Kaplan-Meier survival analysis revealed that the observation group had a higher disease-free survival(DFS)rate at 2 years of follow-up compared to the control group[73.8%(79/107) vs.68.1%(231/339), Log-rank χ2=2.676, P=0.041].Additionally, the median DFS time was longer in the observation group[19(12, 22)months]compared to the control group[16(11, 19)months]( Z=2.774, P=0.038).Furthermore, the observation group exhibited a significantly longer OS time[26(21, 33)months]compared to the control group[22(18, 14)months]( Z=2.879, P=0.032).However, the median PFS time was similar in both groups[20(14, 25)months vs.16(12, 21)months]( Z=1.545, P=0.123).The incidence of distant metastasis was 18.7%(20/107)in the observation group and 20.4%(69/339)in the control group(Log-rank χ2=0.341, P=0.708), indicating no significant difference.Similarly, there was no significant difference in the risk of local recurrence between the observation group[9.3%(10/107)]and the control group[6.5%(22/339)](Log-rank χ2=0.996, P=0.318).In terms of adverse reactions, there was no statistically significant difference in the incidence of grade≥3 acute toxic reactions between the two groups[19.6%(21/107) vs.12.1%(41/339), Log-rank χ2=1.661, P=0.148].A multifactorial Cox regression analysis revealed that age( HR=0.586, P=0.005), ECOG score( HR=0.721, P=0.028), MRI T-stage( HR=0.605, P=0.008), rectal mesenteric fascial infiltration( HR=1.649, P=0.012), and distance from the external anal verge( HR=0.638, P=0.041)were associated with DFS. Conclusions:The findings indicate that the combination of preoperative short-course radiotherapy and neoadjuvant chemotherapy in elderly patients with locally advanced rectal cancer demonstrates favorable short-term effectiveness and safety.This approach shows promise in improving outcomes for elderly patients with locally advanced rectal cancer.

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues. Magnesium has been proved to promote bone healing under normal conditions. Here, we elucidate the mechanism by which Mg²⁺ promotes angiogenesis and osseointegration in diabetic status. We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised, with significantly decreased angiogenesis. We then developed Mg-coating implants with hydrothermal synthesis. These implants successfully improved the vascularization and osseointegration in diabetic status. Mechanically, Mg²⁺ promoted the degradation of Kelch-like ECH-associated protein 1 (Keap1) and the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) by up-regulating the expression of sestrin 2 (SESN2) in endothelial cells, thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia. Altogether, our data suggested that Mg²⁺ promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.
Mice ; Animals ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Magnesium/metabolism* ; Osseointegration ; Diabetes Mellitus, Experimental/metabolism* ; Endothelial Cells/metabolism* ; NF-E2-Related Factor 2/metabolism*

Objective:To investigate the clinical value of the novel approach,radical resection of the retroperitoneal lipo-lymphatic layer (RRRLLL),in the surgical treatment of resectable pancreatic head cancer.Methods:Between June 2020 and June 2022,a total of 221 patients with pancreatic head cancer underwent surgical treatment using the RRRLLL approach(RRRLLL group),while 107 patients received traditional surgical treatment(traditional group) in five high-volume pancreatic centers in China. Data from surgical technique and clinical perioperative outcomes,including lymph node harvested,surgical time,and complications,were analyzed. The RRRLLL group consisted of 144 males and 77 females with an age of (67.5±9.0) years(range:41.3 to 81.1 years). The traditional group included 71 males and 36 females,with an age of (66.3±8.1) years(range:45.1 to 79.2 years). Statistical analysis was performed using the K-S test, Z test,or χ 2 test, respectively. Results:Pancreaticoduodenectomy was performed successfully in all patients,achieving R0 resection. RRRLLL group surgery required mobilization of retroperitoneal adipose and lymphatic tissues starting from the right edge of the inferior vena cava and extending to the left side,up to the superior mesenteric artery,down to the inferior mesenteric artery,and left to the left side of the aorta,including the perineural and lymphatic tissues around the superior mesenteric artery and the sheath of the mesenteric artery. However,the traditional group did not include the areas mentioned above in the scope of clearance. There were no statistically significant differences between the RRRLLL group and the traditional group in terms of age,sex,tumor size,T stage,and vascular invasion (all P>0.05). However,the number of lymph nodes harvested in the RRRLLL group was significantly higher at 28.7±9.0 (range: 18 to 39) compared to 18.2±8.0 (range: 12 to 21) in the traditional group ( Z=-10.691, P<0.05). There were no statistically significant differences in the number of positive lymph nodes,N staging,and postoperative complications between the two groups. Conclusion:The RRRLLL approach improved lymph node dissection compared to the traditional approach,potentially leading to reduced recurrence rates.

Objective:To investigate the clinical value of the novel approach,radical resection of the retroperitoneal lipo-lymphatic layer (RRRLLL),in the surgical treatment of resectable pancreatic head cancer.Methods:Between June 2020 and June 2022,a total of 221 patients with pancreatic head cancer underwent surgical treatment using the RRRLLL approach(RRRLLL group),while 107 patients received traditional surgical treatment(traditional group) in five high-volume pancreatic centers in China. Data from surgical technique and clinical perioperative outcomes,including lymph node harvested,surgical time,and complications,were analyzed. The RRRLLL group consisted of 144 males and 77 females with an age of (67.5±9.0) years(range:41.3 to 81.1 years). The traditional group included 71 males and 36 females,with an age of (66.3±8.1) years(range:45.1 to 79.2 years). Statistical analysis was performed using the K-S test, Z test,or χ 2 test, respectively. Results:Pancreaticoduodenectomy was performed successfully in all patients,achieving R0 resection. RRRLLL group surgery required mobilization of retroperitoneal adipose and lymphatic tissues starting from the right edge of the inferior vena cava and extending to the left side,up to the superior mesenteric artery,down to the inferior mesenteric artery,and left to the left side of the aorta,including the perineural and lymphatic tissues around the superior mesenteric artery and the sheath of the mesenteric artery. However,the traditional group did not include the areas mentioned above in the scope of clearance. There were no statistically significant differences between the RRRLLL group and the traditional group in terms of age,sex,tumor size,T stage,and vascular invasion (all P>0.05). However,the number of lymph nodes harvested in the RRRLLL group was significantly higher at 28.7±9.0 (range: 18 to 39) compared to 18.2±8.0 (range: 12 to 21) in the traditional group ( Z=-10.691, P<0.05). There were no statistically significant differences in the number of positive lymph nodes,N staging,and postoperative complications between the two groups. Conclusion:The RRRLLL approach improved lymph node dissection compared to the traditional approach,potentially leading to reduced recurrence rates.

The dorsal lingual epithelium, which is composed of taste buds and keratinocytes differentiated from K14⁺ basal cells, discriminates taste compounds and maintains the epithelial barrier. N6-methyladenosine (m⁶A) is the most abundant mRNA modification in eukaryotic cells. How METTL3-mediated m⁶A modification regulates K14⁺ basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear. Here we show knockout of Mettl3 in K14⁺ cells reduced the taste buds and enhanced keratinocytes. Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds. Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization, but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery. Mechanically, we revealed that the most frequent m⁶A modifications were enriched in Hippo and Wnt signaling, and specific peaks were observed near the stop codons of Lats1 and FZD7. Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.
Animals ; Epithelium/metabolism* ; Homeostasis ; Methylation ; Methyltransferases/metabolism* ; Mice ; RNA ; Taste Buds/metabolism*

Objective:To explore clinicopathological features and prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in children induced by antithyroid drugs.Methods:The clinicopathological features, treatment and prognosis of 3 children with AAV induced by antithyroid drugs in the Department of Pediatric Nephrology and Rheumatology of the First Affiliated Hospital of Sun Yat-sen University were analyzed retrospectively, and the literatures were reviewed.Results:(1) Among the 3 cases, there were 2 females and 1 male, whose ages were 12.6, 13.9 and 13.1 years old, respectively. All patients had medication history of propylthiouracil (PTU) and/or methimazole (MMI) before onset. Initial manifestation was pallor and renal involvements with nephrotic proteinuria, hematuria and renal function abnormality, while 2 of them had hypertension. Extrarenal manifestations were also presented: case 1 presented with rash, arthralgia and cardiac insufficiency; case 2 had brain involvement with repeated convulsions; case 3 presented with arthralgia and lung involvement. They were all tested positive for p-ANCA and MPO-ANCA. Initial renal histopathology of the 3 cases were consistent with ANCA-associated glomerulonephritis, which were classified into sclerosis, crescentic and mixed class respectively. After 8 months of treatments, repeated renal biopsy of case 3 had demonstrated progression to sclerosis class. Antithyroid drugs (PTU or MMI) were discontinued in 3 cases, and the children were all treated with corticosteroid combined with intravenous pulse cyclophosphamide therapy. Plasma exchange was performed in case 2 and case 3 due to rapidly progressive glomerulonephritis and disease recurrence (suspected pulmonary hemorrhage), respectively. Case 3 was treated with rituximab combined with mycophenolate mofetil after recurrence. The extrarenal symptoms relieved quickly after treatments in all cases. P-ANCA and MPO-ANCA became negative in case 1 and case 2 after 6 months of treatments but they were persistently positive in case 3. Three cases were followed up for 24 months, 10 months and 12 months, respectively: case 1 develop chronic kidney disease (CKD) stage 2 with normal urinalysis; case 2 develop CKD stage 5 and had sudden death at home at 10-month follow-up; case 3 develop CKD stage 4 with nephrotic proteinuria and microscopic hematuria. (2) There were totally 30 pediatric cases with AAV induced by PTU and MMI, including 27 reported cases in the literature and 3 cases in this study. Symptoms of AAV appeared in children after an average administration of (37.5±4.0) months of PTU (range from one month to 96 months and 8 months of MMI alone). Kidney (28 cases, 93.3%) and lung (12 cases, 40.0%) were commonly involved, while brain (2 cases, 6.7%) was rarely involved. The pathological changes of kidney were crescent nephritis (5/23) and necrotizing pauci-immune complex nephritis (11/23). The total remission rate was 93.3% (28/30) after antithyroid drugs withdrawal and treatment with corticosteroids and immunosuppressive therapy, however, there were still severe cases with progression to CKD stage 5, and death. (3) Thirty cases were divided into complete response group ( n=19) and incomplete response group ( n=11) according to the treatment response. Compared with complete response group, the proportions of massive proteinuria (8/11 vs 5/19), fibrinoid necrosis (7/9 vs 4/14), deposition of immune complex in renal tissues (6/9 vs 2/14) and administration of immunosuppressants (10/11 vs 5/19), and degree of tubular atrophy (0/1/2/3 grade, 2/4/2/1 vs 9/5/0/0) in incomplete response group were higher (all P<0.05). Conclusions:PTU and MMI can both induce AAV in children, and AAV may occur after short-term course of administration. Kidney and lung are commonly involved while brain involvement is rarely seen. Timely withdrawal of antithyroid drugs and proper treatments with corticosteroids and immunosuppressants can result in high remission rate, though there are still some severe cases. Nephrotic-range proteinuria, renal fibrinoid necrosis, immune-complex deposition and tubular atrophy may be the risk factors of AAV for poor prognosis.

Tooth root morphogenesis involves two biological processes, root elongation and dentinogenesis, which are guaranteed by downgrowth of Hertwig's epithelial root sheath (HERS) and normal odontoblast differentiation. Ubiquitin-dependent protein degradation has been reported to precisely regulate various physiological processes, while its role in tooth development is still elusive. Here we show ubiquitin-specific protease 34 (USP34) plays a pivotal role in root formation. Deletion of Usp34 in dental mesenchymal cells leads to short root anomaly, characterized by truncated roots and thin root dentin. The USP34-deficient dental pulp cells (DPCs) exhibit decreased odontogenic differentiation with downregulation of nuclear factor I/C (NFIC). Overexpression of NFIC partially restores the impaired odontogenic potential of DPCs. These findings indicate that USP34-dependent deubiquitination is critical for root morphogenesis by stabilizing NFIC.
Cell Differentiation ; Female ; Morphogenesis ; NFI Transcription Factors ; Odontogenesis ; Tooth Root

Objective To investigate the clinical efficacy of modified Takada procedure duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD) for the treatment of pancreatic head lesions.Methods 6 cases of DPPHR with the modified Takada procedure were compared with 6 cases of classical PD.The clinical data were analyzed,and the short-term prognosis was compared.Results The operation time was(281.7 ±42.6)min in DPPHR group,and(308.3 ±41.1)min in PD group (P ＜ 0.05).The intraoperative blood loss were (300 ± 187) ml in DPPHR group and (270 ± 66) ml in PD group (P ＞ 0.05).The postoperative recovery time to oral food-intake and postoperative hospital stay were (3.7 ± 1.6) days and (6.8 ± 1.7) days in DPPHR group and (9.0 ±4.3) days and(14.8 ±2.1)days in the PD group (P ＜ 0.05).The KPS scores at 3 months and 6 months after operation in DPPHR group (90.0 ± 6.2,96.7 ±5.1) were better than that of the PD group (78.0 ±7.5,90.0 ±6.3) (P ＜0.05).There was no significant difference between the two groups in the complication rate and recurrence rate in this period of time(P ＞ 0.05).Conclusion DPPHR with the modified Takada procedure is safe and effective for the treatment of pancreatic head lesions.

Objective To study the relationships of TGFβ1 (-509C/ T, +869T/ C) and TGFβR2 (-875 G/ A) single nucleotide polymorphisms (SNPs) with colorectal cancer (CRC) in Chinese Han popu-lation in Shandong. Methods TGFβ1 -509C/ T and +869T/ C SNPs in a total of 490 patients with CRC were detected using gene chip. TGFβR2 -875 SNPs was analyzed using PCR-RFLP. TGFβ1 concentrations in serum samples were measured by ELISA. Immunohistochemistry was used to detect the expression of TGFβR2. The relationships of TGFβ1 (-509C/ T, +869T/ C) and TGFβR2 (-875 G/ A) SNPs with CRC were analyzed through a case-control study. Chi-square test or t test was used for statistical analysis. Rela-tive risk was estimated by odds ratio (OR) and 95％ confidence interval (95％ CI). Results No signifi-cant difference in genotype or allele frequency at TGFβ1 -509 / +869 was found between patients with CRC and healthy subjects (P>0. 05). The frequencies of TGFβR2 -875GG genotype and -875G allele in pa-tients with CRC were significantly higher than those in healthy subjects (-875GG: χ2 = 4. 65, P = 0. 031, OR=1. 32, 95％ CI=1. 03-1. 71; -875G: χ2 =4. 95, P=0. 026, OR=1. 29, 95％ CI=1. 03-1. 61). Com-pare with the healthy control group, higher frequencies of TGFβR2 -875GG genotype and -875G allele were also detected in rectal cancer ( -875GG: P = 0. 04, OR = 1. 39, 95％ CI = 1. 02-1. 95 and -875G: P =0. 045, OR=1. 32, 95％ CI = 1. 01-1. 73), tubular adenocarcinoma ( -875GG: P = 0. 004, OR = 1. 51, 95％ CI=1. 14-2. 00 and -875G: P=0. 003, OR=1. 45, 95％ CI=1. 14-1. 85) and highly differentiated tu-bular adenocarcinoma (-875GG: P=0. 003, OR=1. 68, 95％ CI=1. 19-2. 38 and -875G: P=0. 002, OR=1. 62, 95％ CI=1. 18-2. 21) groups. The serum TGFβ1 levels in TGFβR2 -875G carriers with CRC were significantly higher than those in TGFβR2 -875AA carriers in both CRC (t= -3. 42, P<0. 05) and healthy control (t= -5. 09, P<0. 001) groups. TGFβR2 expression in -875G carriers with rectal cancer was signifi-cantly lower than that in -875AA carriers with rectal cancer (P=0. 047) and healthy subjects (P=0. 027).Conclusion TGFβR2 -875GG might be a potential risk factor for CRC in Chinese Han population in Shandong and TGFβR2 - 875G might be a risk factor for rectal cancer and highly differentiated tubular adenocarcinoma.

Objective To study the correlations between genetic polymorphisms of TNF-α as well as IL-6 and susceptibility to colorectal cancer among Chinese Han people in Shandong province.Methods Single nucleotide polymorphisms (SNPs) of TNF-α-238G/A,-308G/A and IL-6-174G/C,-572G/C,-597G/A in 490 patients with colorectal cancer were analyzed by using gene chip.Concentrations of TNF-α and IL-6 in serum samples were measured by ELISA.A case-control study was conducted to analyze the correlations between SNPs of TNF-α-238G/A,-308G/A as well as IL-6-174G/C,-572G/C,-597G/A and susceptibility to colorectal cancer.Chi-square test or t test was used for statistical analysis.Relative risks were estimated based on the values of odds ratio (OR) and 95% confidence interval (95%CI).Results The frequency of TNF-α-308AA in patients with colorectal cancer was significantly higher than that in healthy subjects (x2 =6.15, P<0.05, OR=2.08, 95%CI=1.17-3.71), while the frequency of IL-6-572CC in patients with colorectal cancer was significantly lower than that in healthy subjects (x2 =4.97, P<0.05, OR=0.73, 95%CI=0.55-0.96).The frequency of TNF-α-308AA in patients with colon cancer (OR=2.31, 95%CI=1.17-4.55), tubular adenocarcinoma (OR=2.32, 95%CI=1.28-4.21), high (OR=2.05, 95%CI=1.01-4.15) or moderately differentiated adenocarcinoma (OR=5.88, 95%CI=1.79-19.30) was significantly higher than that in healthy subjects.The levels of serum TNF-α in TNF-α-308AA carriers with colorectal cancer were significantly higher than those in TNF-α-308G carriers with colorectal cancer (t=2.13, P<0.05) as well as those in healthy TNF-α-308AA carriers (t=2.13, P<0.05).The levels of serum IL-6 in colorectal cancer group were significantly higher than those in control group (t=6.74, P<0.001).Conclusion The SNPs of TNF-α-308 and IL-6-572 are associated with the occurrence and development of colorectal cancer in Chinese Han people in Shandong province.